Compositions and methods for inhibiting gene expression of LPA

ABSTRACT

RNA interference (RNAi) agents and RNAi agent conjugates for inhibiting the expression of the LPA (apo(a)) gene are described. Pharmaceutical compositions comprising one or more LPA RNAi agents optionally with one or more additional therapeutics are also described. Delivery of the described LPA RNAi agents to liver cells in vivo provides for inhibition of LPA gene expression and treatment of cardiovascular and cardiovascular-related diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/281,309, filed Sep. 30, 2016, which claims the benefit of U.S.Provisional Application No. 62/383,221, filed Sep. 2, 2016; U.S.Provisional Application No. 62/346,304, filed Jun. 6, 2016; and U.S.Provisional Application No. 62/235,816, filed Oct. 1, 2015, all of whichare hereby incorporated by reference in their entireties.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The present application contains a Sequence Listing, which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. The computer readable format copy of theSequence Listing, which was created on Feb. 21, 2018, is namedA-2132-US-CNT_SeqList.txt and is 610 kilobytes in size.

BACKGROUND

Lipoprotein(a) [Lp(a)] is a heterogeneous low density lipoprotein(LDL)-like particle containing a lipid core and apolipoprotein B(apoB-100) with a unique constituent, apolipoprotein (a) (apo(a)), thatis attached to apoB-100 through a disulfide bond.

The apo(a) gene (LPA) is expressed predominantly in the liver andexpression is restricted to human and non-human primates. Lp(a) levelsin humans are genetically defined and do not change significantly withdiet, exercise, or other lifestyle changes. LPA4 varies in lengthdepending upon the number of Kringle KIV2 domains present and itsexpression is inversely correlated with the number of domains present.Normal Lp(a) levels range from 0.1-25 mg/dl, with about 25% of thepopulation in the United States of America having Lp(a) levels of 30mg/dl or higher.

Analysis of Lp(a) levels in multiple studies have implicated high Lp(a)levels as an independent risk factor for cardiovascular disease, stroke,and other related disorders including atherosclerotic stenosis. Inaddition, genome-wide association analyses have also implicated LPA as agenetic risk factor for diseases such as atherosclerotic stenosis.

When therapeutic lipoprotein apheresis is used to lower both Lp(a) andLDL levels in hyperlipidemic patients, significant reductions ofcardiovascular events have been observed. Therefore there exists a needfor therapeutics and treatments related to these and other LPA-relateddiseases.

SUMMARY

Described herein are LPA (also termed apo(a)) RNA interference (RNAi)agents (also termed RNAi trigger, or trigger) and compositionscontaining LPA RNAi agents for selectively and efficiently inhibitingexpression of the LPA gene. LPA is the name of the gene which encodesapolipoprotein (a) (apo(a)), a key component of the lipoprotein (a)particle (Lp(a)). The LPA RNAi agents described herein can be used inthe prevention or treatment or the preparation of a medicament for theprevention or treatment of diseases including, but not limited to:Berger's disease, peripheral artery disease, coronary artery disease,metabolic syndrome, acute coronary syndrome, aortic valve stenosis,aortic valve regurgitation, aortic dissection, retinal artery occlusion,cerebrovascular disease, mesenteric ischemia, superior mesenteric arteryocclusion, renal artery stenosis, stable/unstable angina, acute coronarysyndrome, heterozygous or homozygous familial hypercholesterolemia,hyperapobetalipoproteinemia, cerebrovascular atherosclerosis,cerebrovascular disease, and venous thrombosis.

Each LPA RNAi agent includes at least a sense strand and an antisensestrand. The sense strand and the antisense strand can be partially,substantially, or fully complementary to each other. The length of theRNAi agent sense and antisense strands described herein each can be 17to 30 nucleotides in length. In some embodiments, the sense andantisense strands are independently 17 to 26 nucleotides in length. Thesense and antisense strands can be either the same length or differentlengths. The RNAi agents described herein, upon delivery to a cellexpressing the LPA gene, inhibit the expression of the LPA gene in vitroor in vivo.

A sense strand of an LPA RNAi agent comprises a nucleotide sequencehaving at least 90% identity over a core stretch of at least 17consecutive nucleotides to a sequence in an LPA mRNA. In someembodiments, the sense strand nucleotide sequence having at least 90%identity to a sequence in the LPA mRNA is 17, 18, 19, 20, 21, 22, or 23nucleotides in length. An antisense strand of an LPA RNAi agentcomprises a nucleotide sequence having at least 90% complementary over acore stretch of at least 16 consecutive nucleotides to a sequence in theLPA mRNA and the corresponding sense strand. In some embodiments, theantisense strand nucleotide sequence having at least 90% complementarityto a sequence in the LPA mRNA or the corresponding sense strand is 17,18, 19, 20, 21, 22, or 23 nucleotides in length.

In some embodiments, one or more LPA RNAi agents are delivered to targetcells or tissues using any oligonucleotide delivery technology known inthe art. Nucleic acid delivery methods include, but are not limited to,by encapsulation in liposomes, by iontophoresis, or by incorporationinto other vehicles, such as hydrogels, cyclodextrins, biodegradablenanocapsules, and bioadhesive microspheres, proteinaceous vectors orDynamic Polyconjugates™ (DPCs (see, for example WO 2000/053722, WO2008/0022309, WO 2011/104169, and WO 2012/083185, each of which isincorporated herein by reference). In some embodiments, an LPA RNAiagent is conjugated to a targeting group. In some embodiments, thetargeting group can include a cell receptor ligand, such as a galactosecluster, including a galactose cluster comprising anN-acetyl-galactosamine trimer.

In some embodiments are described pharmaceutical compositions comprisingone or more LPA RNAi agents. In some embodiments, an LPA RNAi agent isoptionally combined with one or more additional (i.e., second, third,etc.) therapeutics. An additional therapeutic can be another LPA RNAiagent (e.g., an LPA RNAi agent which targets a different sequence withinthe LPA target). An additional therapeutic can also be a small moleculedrug, antibody, antibody fragment, and/or vaccine. The LPA RNAi agents,with or without the one or more additional therapeutics, can be combinedwith one or more excipients to form pharmaceutical compositions.

In some embodiments, compositions for delivering an LPA RNAi agent to aliver cell, particularly hepatocytes, in vivo are described, comprising:an LPA RNAi agent conjugated to a targeting group. In some embodiments,the targeting group is a asialoglycoprotein ligand.

Also described are methods of treating a human subject having apathological state or at risk of developing a pathological statemediated at least in part by LPA expression, the methods comprising thestep(s) of administering to the subject a therapeutically effectiveamount of an LPA RNAi agent or LPA RNAi agent-containing composition.The method of treating a subject with an LPA RNAi agent or LPA RNAiagent-containing composition can optionally be combined with one or moresteps of administering one or more additional (i.e., second)therapeutics or treatments. The LPA RNAi agent and additionaltherapeutics can be administered in a single composition or they may beadministered separately. Examples of additional therapeutics include,but are not limited to, HMg Co-A reductase inhibitors (statins),ezetimibe. PCSK-9 inhibitors, CTEP inhibitors, therapies targetingANGPTL3, therapies targeting APOC3, and niacin.

Use of the described LPA RNAi agents can be used in methods fortherapeutic prevention or treatment of diseases including, but notlimited to: Berger's disease, peripheral artery disease, coronary arterydisease, metabolic syndrome, acute coronary syndrome, aortic valvestenosis, aortic valve regurgitation, aortic dissection, retinal arteryocclusion, cerebrovascular disease, mesenteric ischemia, superiormesenteric artery occlusion, renal artery stenosis, stable/unstableangina, acute coronary syndrome, heterozygous or homozygous familialhypercholesterolemia hyperapobetalipoproteinemia, cerebrovascularatherosclerosis, cerebrovascular disease, and venous thrombosis. Suchmethods comprise administration of an LPA RNAi agent as described hereinto a subject, e.g., a human or animal subject.

The pharmaceutical compositions can be administered in a number of waysdepending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration can be made by any way commonlyknown in the art, such as, but not limited to, topical (e.g., by atransdermal patch), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer, intratracheal, intranasal),epidermal, transdermal, oral or parenteral. Parenteral administrationincludes, but is not limited to, intravenous, intraarterial,subcutaneous, intraperitoneal or intramuscular injection or infusion;subdermal (e.g., via an implanted device), intracranial,intraparenchymal, intrathecal, and intraventricular, administration. Insome embodiments, the pharmaceutical compositions described herein areadministered by subcutaneous injection.

The described LPA RNAi agents and/or compositions can be used in methodsfor therapeutic treatment of diseases, including but not limited to:Berger's disease, peripheral artery disease, coronary artery disease,metabolic syndrome, acute coronary syndrome, aortic valve stenosis,aortic valve regurgitation, aortic dissection, retinal artery occlusion,cerebrovascular disease, mesenteric ischemia, superior mesenteric arteryocclusion, renal artery stenosis, stable/unstable angina, acute coronarysyndrome, heterozygous or homozygous familial hypercholesterolemia,hyperapobetalipoproteinemia, cerebrovascular atherosclerosis,cerebrovascular disease, and venous thrombosis. Such methods compriseadministration of an LPA RNAi agent as described herein to a subject,e.g., a human or animal subject.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Graph illustrating serum Lp(a) protein levels in Lp(a)transgenic (Tg) mice following a single subcutaneous administration of0.5 mg/kg (dashed line) or 2 mg/kg (solid line) of indicated LPA RNAiagent. Lp(a) levels were normalized to day 1 and saline control.

FIG. 2. Graph illustrating serum Lp(a) protein levels in Lp(a) Tg micefollowing administration of three subcutaneous doses of 1 mg/kg (dashedline) or 3 mg/kg (solid line) of indicated LPA RNAi agent, administeredonce a week for three weeks (dose on days 1, 8, and 15). Lp(a) levelswere normalized to day 1 and saline control.

FIG. 3. Graph illustrating Lp(a) particle levels in Cynomolgus monkeyserum following administration of a single 2 mg/kg AD01196 LPA RNAiagent dosed 1:1 (wt/wt) with delivery polymer on day 1. Lp(a) levelswere normalized to two pre-dose values (shown as day 0).

FIG. 4. Graph illustrating Lp(a) particle levels in Cynomolgus monkeyserum following administration of 4 mg/kg or 6 mg/kg LPA RNAi agentdosed 1:1 (wt/wt) with delivery polymer on day 1 and day 71. Lp(a)levels were normalized to two pre-dose values (shown as day 0). 4 mg/kgdose=black circles; 6 mg/kg dose=gray squares.

FIG. 5. Graph illustrating Lp(a) particle levels in Cynomolgus monkeyserum following three weekly subcutaneous doses of 3 mg/kg of AD02819LPA RNAi agent on days 1, 8, and 15. Lp(a) levels were normalized tothree pre-dose values (shown as day 0).

FIG. 6. Graph illustrating Lp(a) particle levels in Cynomolgus monkeyserum following a single subcutaneous administration of 3 mg/kg of LPARNAi agent on day 1. AD03460 and AD03536 groups received an additional 1mg/kg dose of LPA RNAi agent on day 48. Lp(a) levels were normalized tothree pre-dose values (shown as day 0).

DETAILED DESCRIPTION

Described herein are RNAi agents for inhibiting expression of the LPAgene (referred to herein as LPA RNAi agents). The RNAi agents describedherein, upon delivery to a cell expressing the LPA gene, inhibit orknockdown expression of LPA in vitro and/or in vivo through thebiological process of RNA interference (RNAi). As used herein, unlessspecifically noted otherwise, LPA may refer to an LPA gene, an LPA mRNA,or an LP(a) protein, as appropriate.

An LPA RNAi agent comprises a sense strand and an antisense strand. Thesense strand and antisense strand each contain a core sequence 17-23nucleobases in length. An antisense strand core sequence is 100%(perfectly) complementary or at least 90% (substantially) complementaryto a nucleotide sequence (sometimes referred to, e.g., as a targetsequence) present in an LPA mRNA. A sense strand core sequence is 100%(perfectly) complementary or at least 90% (substantially) complementaryto a sequence in the antisense strand and thus the sense strand coresequence is perfectly identical or at least 90% identical to anucleotide sequence (target sequence) present in the LPA mRNA. A sensestrand core sequence can be the same length as a corresponding antisensecore sequence or it can be a different length. In some embodiments, theantisense strand core sequence is 17, 18, 19, 20, 21, 22, or 23nucleotides in length. In some embodiments, the sense strand coresequence is 17, 18, 19, 20, 21, 22, or 23 nucleotides in length.

LPA RNAi agent sense and antisense strands anneal to form a duplex. Asense strand and an antisense strand of an LPA RNAi agent are partially,substantially, or fully complementary to each other. Within thecomplementary duplex region, the sense strand core sequence is at least90% complementary or 100% complementary to the antisense core sequence.In some embodiments, the sense strand core sequence contains a sequenceof at least 17, at least 18, at least 19, at least 20, or at least 21nucleotides that is at least 90% or 100% complementary to acorresponding 17, 18, 19, 20, or 21 nucleotide sequence of the antisensestrand core sequence (i.e., the sense strand and antisense coresequences of an LPA RNAi agent have a region of at least 17, at least18, at least 19, at least 20, or at least 21 nucleotides that is atleast 90% base paired or 100% base paired.)

As used herein, and unless otherwise indicated, the term“complementary,” when used to describe a first nucleotide sequence(e.g., RNAi agent sense strand or LPA mRNA) in relation to a secondnucleotide sequence (e.g., RNAi agent antisense strand), refers to theability of an oligonucleotide or polynucleotide comprising the firstnucleotide sequence to hybridize (form base pair hydrogen bonds) andform a duplex or double helical structure under certain conditions withan oligonucleotide or polynucleotide comprising the second nucleotidesequence. Complementary sequences include Watson-Crick base pairs ornon-Watson-Crick base pairs and include natural or modified nucleotidesor nucleotide mimics as long as the above requirements with respect totheir ability to hybridize are fulfilled. “Perfectly complementary” or“fully complementary” means that all (100%) of the bases in a contiguoussequence of a first polynucleotide will hybridize with the same numberof bases in a contiguous sequence of a second polynucleotide. Thecontiguous sequence may comprise all or a part of a first or secondnucleotide sequence. As used herein, “partial complementary” means thatin a hybridized pair of nucleobase sequences, at least 70% of the basesin a contiguous sequence of a first polynucleotide will hybridize withthe same number of bases in a contiguous sequence of a secondpolynucleotide. As used herein, “substantial complementary” means thatin a hybridized pair of nucleobase sequences, at least 85% of the basesin a contiguous sequence of a first polynucleotide will hybridize withthe same number of bases in a contiguous sequence of a secondpolynucleotide. The terms “complementary”, “fully complementary” and“substantially complementary” as used herein may be used with respect tothe base matching between the sense strand and the antisense strand ofan RNAi agent, or between the antisense strand of an RNAi agent and asequence of an LPA mRNA. Sequence identity or complementarity isindependent of modification. For the purposes of determining identity orcomplementarity, for example, a and Af are complementary to U (or T) andidentical to A.

The length of the LPA RNAi agent sense and antisense strands describedherein are independently 17 to 30 nucleotides in length. In someembodiments, the sense and antisense strands are independently 17 to 26nucleotides in length. In some embodiments, the sense and antisensestrands are 19-26 nucleotides in length. In some embodiments, thedescribed RNAi agent sense and antisense strands are independently 17,18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides in length. The senseand antisense strands can be either the same length or they can bedifferent lengths. In some embodiments, a sense strand and an antisensestrand are each 26 nucleotides in length. In some embodiments, a sensestrand is 23 nucleotides in length and an antisense strand is 21nucleotides in length. In some embodiments, a sense strand is 22nucleotides in length and an antisense strand is 21 nucleotides inlength. In some embodiments, a sense strand is 21 nucleotides in lengthand an antisense strand is 21 nucleotides in length. In someembodiments, a sense strand is 19 nucleotides in length and an antisensestrand is 21 nucleotides in length.

The sense strand and/or the antisense strand may optionally andindependently contain an additional 1, 2, 3, 4, 5, or 6 nucleotides(extension) at the 3′ end, the 5′ end, or both the 3′ and 5′ ends of thecore sequences. The antisense strand additional nucleotides, if present,may or may not be complementary to the corresponding sequence in the LPAmRNA. The sense strand additional nucleotides, if present, may or maynot be identical to the corresponding sequence in the LPA mRNA. Theantisense strand additional nucleotides, if present, may or may not becomplementary to the corresponding sense strand's additionalnucleotides, if present.

As used herein, an extension comprises 1, 2, 3, 4, 5, or 6 nucleotidesat the 5′ and/or 3′ end of the sense strand core sequence and/orantisense strand core sequence. The extension nucleotides on a sensestrand may or may not be complementary to nucleotides, either coresequence nucleotides or extension nucleotides, in the correspondingantisense strand. Conversely, the extension nucleotides on an antisensestrand may or may not be complementary to nucleotides, either coresequence nucleotides or extension nucleotides, in the correspondingsense strand. In some embodiments, both the sense strand and theantisense strand of an RNAi agent contain 3′ and 5′ extensions. In someembodiments, one or more of the 3′ extension nucleotides of one strandbase pairs with one or more 5′ extension nucleotides of the otherstrand. In other embodiments, one or more of 3′ extension nucleotides ofone strand do not base pair with one or more 5′ extension nucleotides ofthe other strand. In some embodiments, an LPA RNAi agent has anantisense strand having a 3′ extension and a sense strand having a 5′extension.

In some embodiments an LPA RNAi agent comprises an antisense strandhaving a 3′ extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. Inother embodiments, an LPA RNAi agent comprises an antisense strandhaving a 3′ extension of 1, 2, or 3 nucleotides in length. In someembodiments, one or more of the antisense strand extension nucleotidescomprise uracil or thymidine nucleotides or nucleotides which arecomplementary to the corresponding LPA mRNA sequence. In someembodiments, a 3′ antisense strand extension includes or consists of,but is not limited to: Ab, AbAb, AUA, UGCUU, CUG, UG, UGCC, CUGCC, CGU,CUU, UGCCUA, CUGCCU, UGCCU, UGAUU, GCCUAU, T, TT (each listed 5′ to 3′).

In some embodiments, an LPA RNAi agent comprises an antisense strandhaving a 5′ extension of 1, 2, 3, 4, or 5 nucleotides in length. Inother embodiments, an LPA RNAi agent comprises an antisense strandhaving a 5′ extension of 1 or 2 nucleotides in length. In someembodiments, one or more of the antisense strand extension nucleotidescomprises uracil or thymidine nucleotides or nucleotides which arecomplementary to the corresponding LPA mRNA sequence. In someembodiments, the 5′ antisense strand extension includes or consists of,but is no limited to, UA, TU, U, T, CUC (each listed 5′ to 3′). Anantisense strand may have any of the 3′ extensions described above incombination with any of the 5′ antisense strand extensions described, ifpresent.

In some embodiments, an LPA RNAi agent comprises a sense strand having a3′ extension of 1, 2, 3, 4, or 5 nucleotides in length. In someembodiments, one or more of the sense strand extension nucleotidescomprises adenosine, uracil, or thymidine nucleotides, AT dinucleotide,or nucleotides which correspond to nucleotides in the LPA mRNA sequence.In some embodiments, the 3′ sense strand extension includes or consistsof, but is no limited to: T, UUAb, UAb, Ab, UT, TT, UUT, TTT, or TITTT(each listed 5′ to 3′).

In some embodiments, an LPA RNAi agent comprises a sense strand having a5′ extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In someembodiments, one or more of the sense strand extension nucleotidescomprise uracil or adenosine nucleotides or nucleotides which correspondto nucleotides in the LPA mRNA sequence. In some embodiments, the sensestrand 5′ extension can be, but is not limited to: CA, AUAGGC, AUAGG,AUAG, AUA, A, AA, AC, GCA, GGCA, GGC, UAUCA, UAUC, Ab, UCA, UAU (eachlisted 5′ to 3′). A sense strand may have a 3′ extension and/or a 5′extension.

Examples of nucleotide sequences used in forming LPA RNAi agents areprovided in Tables 1, 2A, 2B, 3A, and 3B. As used herein, the term“sequence” or “nucleotide sequence” refers to a succession or order ofnucleobases, nucleotides, and/or nucleosides, whether modified orunmodified, described with a succession of letters using the standardnucleotide nomenclature and the key for modified nucleotides describedherein.

RNAi agents include, but are not limited to: short interfering RNAs(siRNAs), double-strand RNAs (dsRNA), micro RNAs (miRNAs), short hairpinRNAs (shRNA), and dicer substrates (e.g., U.S. Pat. Nos. 8,084,599,8,349,809, and 8,513,207).

Unmodified LPA RNAi agent sense strand and antisense strand sequencesare provided in Table 1. In forming LPA RNAi agents, each of thenucleotides in each of the sequences listed in Table 1 may be a modifiednucleotide.

TABLE 1 Unmodified LPA RNAi agentantisense strand and sense strand sequences. Antisense strand base SEQSense strand base SEQ sequence 5′ → 3′ ID NO. sequence 5′ → 3′ ID NO.TCGGCAGUCCCUUCUGCGUTT 1 ACGCAGAAGGGACUGCCGAT 190 TGUAGCACUCCUGCACCCCTT 2GGGGUGCAGGAGUGCUACAT 191 TAAUAAGGGGCUGCCACAGTT 3 CUGUGGCAGCCCCUUAUUAT192 TUAACAAUAAGGGGCUGCCTT 4 GGCAGCCCCUUAUUGUUAAT 193TGUAUAACAAUAAGGGGCUTT 5 AGCCCCUUAUUGUUAUACAT 194 TCGUAUAACAAUAAGGGGCTT 6GCCCCUUAUUGUUAUACGAT 195 TCGUCUGAGCAUUGUGUCATT 7 UGACACAAUGCUCAGACGAT196 TGCGUCUGAGCAUUGUGUCTT 8 GACACAAUGCUCAGACGCAT 197TUGCGUCUGAGCAUUGUGUTT 9 ACACAAUGCUCAGACGCAAT 198 TUCUGCGUCUGAGCAUUGUTT10 ACAAUGCUCAGACGCAGAAT 199 TGGAUCUGGAUUUCGGCAGTT 11CUGCCGAAAUCCAGAUCCAT 200 TCAGGAUCUGGAUUUCGGCTT 12 GCCGAAAUCCAGAUCCUGAT201 TCAUCUGAGCAUCGUGUCATT 13 UGACACGAUGCUCAGAUGAT 202TGCAUCUGAGCAUCGUGUCTT 14 GACACGAUGCUCAGAUGCAT 203 TUGCAUCUGAGCAUCGUGUTT15 ACACGAUGCUCAGAUGCAAT 204 TUCUGCAUCUGAGCAUCGUTT 16ACGAUGCUCAGAUGCAGAAT 205 TAAAGCCUCUAGGCUUGGATT 17 UCCAAGCCUAGAGGCUUUAT206 TGUACCCCGGGGGUUUCCUTT 18 AGGAAACCCCCGGGGUACAT 207TUGUACCCCGGGGGUUUCCTT 19 GGAAACCCCCGGGGUACAAT 208 TCUGUACCCCGGGGGUUUCTT20 GAAACCCCCGGGGUACAGAT 209 TUCCAUAAUGGUAGUAGCATT 21UGCUACUACCAIUAUGGAAT 210 TGUCCAUAAUGGUAGUAGCTT 22 GCUACUACCAUUAUGGACAT211 TCUCUGUCCAUAAUGGUAGTT 23 CUACCAUUAUGGACAGAGAT 212TCGACUAUGCUGGUGUGGUTT 24 ACCACACCAGCAUAGUCGAT 213 TCCGACUAUGCUGGUGUGGTT25 CCACACCAGCAUAGUCGGAT 214 TUCCGACUAUGCUGGUGUGTT 26CACACCAGCAUAGUCGGAAT 215 TGGUCCGACUAUGCUGGUGTT 27 CACCAGCAUAGUCGGACCAT216 TUUUCUGGGGUCCGACUAUTT 28 AUAGUCGGACCCCAGAAAAT 217TUUUUCUGGGGUCCGACUATT 29 UAGUCGGACCCCAGAAAAAT 218 TGCGAAUCUCAGCAUCUGGTT30 CCAGAUGCUGAGAUUCGCAT 219 TCCAAGGGCGAAUCUCAGCTT 31GCUGAGAUUCGCCCUUGGAT 220 TACCAAGGGCGAAUCUCAGTT 32 CUGAGAUUCGCCCUUGGUAT221 TCACCAAGGGCGAAUCUCATT 33 UGAGAUUCGCCCUUGGUGAT 222TACACCAAGGGCGAAUCUCTT 34 GAGAUUCGCCCUUGGUGUAT 223 TCCUGACACUGGGAUCCAUTT35 AUGGAUCCCAGUGUCAGGAT 224 TUGCAAGGACACUUGAUUCTT 36GAAUCAAGUGUCCUUGCAAT 225 TUUGCAAGGACACUUGAUUTT 37 AAUCAAGUGUCCUUGCAAAT226 TUUGCUCCGUUGGUGCUUCTT 38 GAAGCACCAACGGAGCAAAT 227TAAUGAGCCUCGAUAACUCTT 39 GAGUUAUCGAGGCUCAUUAT 228 TGAAUGAGCCUCGAUAACUTT40 AGUUAUCGAGGCUCAUUCAT 229 TGGAUAAUAUUCUGUUGUCTT 41GACAACAGAAUAUUAUCCAT 230 TCCAUGGUAUAACACCAAGTT 42 CUUGGUGUUAUACCAUGGAT231 TGAUCCAUGGUAUAACACCTT 43 GGUGUUAUACCAUGGAUCAT 232TAUUGGGAUCCAUGGUAUATT 44 UAUACCAUGGAUCCCAAUAT 233 TCAUUGGGAUCCAUGGUAUTT45 AUACCAUGGAUCCCAAUGAT 234 TACAUUGG6AUCCAUGGUATT 46UACCAUGGAUCCCAAUGUAT 235 TGACAUUGGGAUCCAUGGUTT 47 ACCAUGGAUCCCAAUGUCAT236 TGACAUUGUGUCAG6UUGCTT 48 GCAACCUGACACAAUGUCAT 237TCACUGGACAUUGUGUCAGTT 49 CUGACACAAUGUCCAGU6AT 238 TACUUGAUUCUGUCACUGGTT50 CCAGUGACAGAAUCAAGUAT 239 TGAGAAUGAGCCUCGAUAATT 51UUAUCGAGGCUCAUUCUCAT 240 TCCAUUUGGGUAGUAUUCUTT 52 AGAAUACUACCCAAAUGGAT241 TCACCAUUUGGGUAGUAUUTT 53 AAUACUACCCAAAUGGUGAT 242TCCACCAUUUGGGUAGUAUTT 54 AUACUACCCAAAUGGUGGAT 243 TAUAACACCAAGGGCGAAUTT55 AUUCGCCCUUGGUGUUAUAT 244 TACUGGGAUCCAUGGUAUATT 56UAUACCAUGGAUCCCAGUAT 245 TCACUGGGAUCCAUGGUAUTT 57 AUACCAUGGAUCCCAGUGAT246 TACCACCGUGGGAGUUGUGTT 58 CACAACUCCCACGGUGGUAT 247TCAAGACUGACAUGUUCUUTT 59 AAGAACAUGUCAGUCUUGAT 248 TGGGAGUUGUGAGGACACUTT60 AGUGUCCUCACAACUCCCAT 249 TUCUCAGGUGGUGCUUGUU7T 61AACAAGCACCACCUGAGAAT 250 TCACAGGGCUUUUCUCAGGTT 62 CCUGAGAAAAGCCCUGUGAT251 TGAUGCCAGUGUGGUAUCATT 63 UGAUACCACACUGGCAUCAT 252TUGAUGCCAGUGUGGUAUCTT 64 GAUACCACACUGGCAUCAAT 253 TGACACCUGAUUCUGUUUCTT55 GAAACAGAAUCAGGUGUCAT 254 TGGACACCUGAUUCUGUUUTT 66AAACAGAAUCAGGUGUCCAT 255 TCUAGGACACCUGAUUCUGTT 67 CAGAAUCAGGUGUCCUAGAT256 TAUAAGGGGCUGCCACAGGTT 68 CCUGUGGCAGCCCCUUAUAT 257TAACAAUAAGGGGCUGCCATT 69 UGGCAGCCCCUUAUUGUUAT 258 TGUCCGACUAUGCUGGUGUTT70 ACACCAGCAUAGUCGGACAT 259 TUCUCAGCAUCUGGAUUCCTT 71GGAAUCCAGAUGCUGAGAAT 260 TCGAAUCUCAGCAUCUGGATT 72 UCCAGAUGCUGAGAUUCGAT261 TAAGGGCGAAUCUCAGCAUTT 73 AUGCUGAGAUUCGCCCUUAT 262TUGACACUGGGAUCCAUGGTT 74 CCAUGGAUCCCAGUGUCAAT 263 TCCGUUGGUGCUUCUUCAGTT75 CUGAAGAAGCACCAACGGAT 264 TCUUGAUUCUGUCACUGGATT 76UCCAGUGACAGAAUCAAGAT 265 TCACCGUGGGAGUUGUGAGTT 77 CUCACAACUCCCACGGUGAT266 TUCUAGGACACCUGAUUCUTT 78 AGAAUCAGGUGUCCUAGAAT 267TAGUCUCUAGGACACCUGATT 79 UCAGGUGUCCUAGAGACUAT 268 TCAAUAAGGGGCUGCCACATT80 UAUAGCCCCUUAUUGUUAUACAT 269 TCUGCGUCUGAGCAUUGUGTT 81UAUGCCCCUUAUUGUUAUACGAT 270 TACAGGAUCU6GAUUUCGGTT 82UAUGACACAAUGCUCAGACGCAT 271 TCCGGGGGUUUCCUCAGUCTT 83UAUACACAAUGCUCAGACGCAAT 272 TUGUCCAUAAUGGUAGUAGTT 84UAUUUAUCGAGGCUCAUUCUCAT 273 TUCUGUCCAUAAUGGUAGUTT 85UAUGAAACAGAAUCAGGUGUCAT 274 TACUCUGUCCAUAAUGGUATT 86UAUACACCAGCAUAGUCGGACAT 275 IAACUCUGUCCAUAAUGGUTT 87UAUUCCAGAUGCUGAGAUUCGAT 276 TGGGCGAAUCUCAGCAUCUTT 88UAUAUGCUGAGAUUCGCCCUUAT 277 TAGGGCGAAUCUCAGCAUCTT 89UAUCCAUGGAUCCCAGUGUCAAT 278 TAACACCAAGGGCGAAUCUTT 90UGUGGCAGCCCCUUAUUGAT 279 TAGGACACUUGAUUCUGUCTT 91 CACAAUGCUCAGACGCAGAT280 TGGACCAAGACUGACAUGUTT 92 CCGAAAUCCAGAUCCUGUAT 281TGGUCAGGCCACCAUUUGGTT 93 GACUGAGGAAACCCCCGGAT 282 TAUCCAUGGUAUAACACCATT94 CUACUACCAUUAUGGACAAT 283 TGGGAUCCAUGGUAUAACATT 95ACUACCAUUAUGGACAGAAT 284 TUGGACAUUGUGUCAGGUUTT 96 UACCAUUAUGGACAGAGUAT285 TAUUCUGUCACUGGACAUUTT 97 ACCAUUAUGGACAGAGUUAT 286TGGUGCUUGUUCAGAAACATT 98 AGAUGCUGAGAUUCGCCCAT 287 TGGAGAAUGAGCCUCGAUATT99 GAUGCUGAGAUUCGCCCUAT 288 TGUGGAGAAUGAGCCUCGATT 100AGAUUCGCCCUUGGUGUUAT 289 TCCGUGGGAGUUGUGAGGATT 101 GACAGAAUCAAGUGUCCUAT290 TGGACCACCGUGGGAGUUGTT 102 ACAUGUCAGUCUUGGUCCAT 291TUGCUUGUUCAGAAGGAGCTT 103 CCAAAUGGUGGCCUGACCAT 292 TCUGAUGCCAGUGUGGUAUTT104 UGGUGUUAUACCAUGGAUAT 293 TUAGGACACCUGAUUCUGUTT 105UGUUAUACCAUGGAUCCCAT 294 TCUCUA6GACACCUGAUUCTT 106 AACCUGACACAAUGUCCAAT295 TUCUCUAGGACACCUGAUUTT 107 AAUGUCCAGUGACAGAAUAT 296TGUCUCUAGGACACCUGAUTT 108 UGUUUCUGAACAAGCACCAT 297TGAGAAUGAGCCUCGAUAACUCUUAU 109 UAUCGAGGCUCAUUCUCCAT 298TGACACCUGAUUCUGUUUCUGAGUAU 110 UCGAGGCUCAUUCUCCACAT 299TCGUAUAACAAUAAGGGGCUGCCUAU 111 UCCUCACAACUCCCACGGAT 300TGCGUCUGAGCAUUGUGUCAGGUUAU 112 CAACUCCCACGGUGGUCCAT 301TUGCGUCUGAGCAUUGUGUCAGGUAU 113 GCUCCUUCUGAACAAGCAAT 302TAAGGGCGAAUCUCAGCAUCUGGUAU 114 AUACCACACUGGCAUCAGAT 303UUAACAAUAAGGGGCUGCAb 115 ACAGAAUCAGGUGUCCUAAT 304 UGUAUAACAAUAAGGGGCAb116 GAAUCAGGUGUCCUAGAGAT 305 UCGUAUAACAAUAAGGGGAb 117AAUCAGGUGUCCUAGAGAAT 306 UGCGUCUGAGCAUUGUGUAb 118 AUCAGGUGUCCUAGAGACAT307 UUGCGUCUGAGCAUUGUGAb 119 UAUAUAGUUAUCGAGGCUCAUUCUCA 308UCAGGAUCUGGAUUUCGGAb 120 UAUAUCAGAAACAGAAUCAGGUGUCA 309UUGCAUCUGAGCAUCGUGAb 121 UAUAUCAGCCCCUUAUUGUUAUACGA 310UCGACUAUGCUGGUGUGGAb 122 UAUAUCUGACACAAUGCUCAGACGCA 311UUUUCUGGGGUCCGACUAAb 123 UAUAUUGACACAAUGCUCAGACGCAA 312UGCGAAUCUCAGCAUCUGAb 124 UAUAUAGAUGCUGAGAUUCGCCCUUA 313UUGCAAGGACACUUGAUUAb 125 GCAGCCCCUUAUUGUUAA 314 UAAUGAGCCUCGAUAACUAb 126GCCCCUUAUUGUUAUACA 315 UGAAUGAGCCUCGAUAACAb 127 CCCCUUAUUGUUAUACGA 316UGACAUUGUGUCAGGUUGAb 128 ACACAAUGCUCAGACGCA 317 UGAGAAUGAGCCUCGAUAAb 129CACAAUGCUCAGACGCAA 318 UCCAUUUGGGUAGUAUUCAb 130 CCGAAAUCCAGAUCCUGA 319UCACCAUUUGGGUAGUAUAb 131 CACGAUGCUCAGAUGCAA 320 UGACACCUGAUUCUGUUUAb 132CCACACCAGCAUAGUCGA 321 UGGACACCUGAUUCUGUUAb 133 UAGUCGGACCCCAGAAAA 322UUAACAAUAAGGGGCUGAbAb 134 CAGAUGCUGAGAUUCGCA 323 UGUAUAACAAUAAGGGGAbAb135 AAUCAAGUGUCCUUGCAA 324 UCGUAUAACAAUAAGGGAbAb 136 AGUUAUCGAGGCUCAUUA325 UGCGUCUGAGCAUUGUGAbAb 137 GUUAUCGAGGCUCAUUCA 326UUGCGUCUGAGCAUUGUAbAb 138 CAACCUGACACAAUGUCA 327 UCAGGAUCUGGAUUUCGAbAb139 UAUCGAGGCUCAUUCUCA 328 UUGCAUCUGAGCAUCGUAbAb 140 GAAUACUACCCAAAUGGA329 UCGACUAUGCUGGUGUGAbAb 141 AUACUACCCAAAUGGUGA 330UUUUCUGGGGUCCGACUAbAb 142 AAACAGAAUCAGGUGUCA 331 UGCGAAUCUCAGCAUCUAbAb143 AACAGAAUCAGGUGUCCA 332 UUGCAAGGACACUUGAUAbAb 144 CAGCCCCUUAUUGUUAA333 UAAUGAGCCUCGAUAACAbAb 145 CCCCUUAUUGUUAUACA 334UGAAUGAGCCUCGAUAAAbAb 146 CCCUUAUUGUUAUACGA 335 UGACAUUGUGUCAGGUUAbAb147 CACAAUGCUCAGACGCA 336 UGAGAAUGAGCCUCGAUAbAb 148 ACAAUGCUCAGACGCAA337 UCCAUUUGGGUAGUAUUAbAb 149 CGAAAUCCAGAUCCUGA 338UCACCAUUUGGGUAGUAAbAb 150 ACGAUGCUCAGAUGCAA 339 UGACACCUGAUUCUGUUAbAb151 CACACCAGCAUAGUCGA 340 UGGACACCUGAUUCUGUAbAb 152 AGUCGGACCCCAGAAAA341 UGAGAAUGAGCCUCGAUAACUCUUAU 153 AGAUGCUGAGAUUCGCA 342UGACACCUGAUUCUGUUUCUGAGUAU 154 AUCAAGUGUCCUUGCAA 343UGAGAAUGAGCCUCGAUAACUCTUAU 155 GUUAUCGAGGCUCAUUA 344UCGUAUAACAAUAAGGGGCUGCCUAU 156 UUAUCGAGGCUCAUUCA 345UGAGAAUGAGCCUCGAUAATT 157 AACCUGACACAAUGUCA 346UCGUAUAACAAUAAGGCGCUGCCUAU 158 AUCGAGGCUCAUUCUCA 347UGAGAAUGAGCCUCGATAbAb 159 AAUACUACCCAAAUGGA 348 UGACACCUGAUUCUGTTAbAb160 UACUACCCAAAUGGUGA 349 UCGUAUAACAAUAAGGGGCUGAUU 161 AACAGAAUCAGGUGUCA350 UCGUAUAACAAUAAGGGGCUGCUU 162 ACAGAAUCAGGUGUCCA 351UGAGAAUGAGCCUCGAUAACUCUU 163 UAUAUCAGCGCCUUAUUGUUAUACGA 352UCGUAUAACAAUAAGGGGCUU 164 ATCGAGGCUCAUUCUCA 353 UGUAUAACAAUAAGGGG 165UCAGCCCCUUAUUGUUAUACGAUUAb 354 UCGUAUAACAAUAAGGG 166UCAGCCCCUUAUUGUUAUACGAAb 355 UGAGAAUGAGCCUCGAT 167UAGUUAUCGAGGCUCAUUCUCAUUAb 356 UGACACCUGAUUCUGTT 168AbGCCCCUUAUUGUUAUACGAUUAb 357 TUCGUAUAACAAUAAGGGGCUGCCUA 169AUAUCAGCCCCUUAUUGUUAUACGAT 358 UAUCGUAUAACAAUAAGGGGCUGCCU 170UAUCAGCCCCUUAUUGUUAUACGAUT 359 TCCGUAUAACAAUAAGGGGCUGCCUA 171AUAUAGUUAUCGAGGCUCAUUCUCAT 360 CUCCGUAUAACAAUAAGGGGCUGCCU 172UAUAGUUAUCGAGGCUCAUUCUCAUT 361 TUGAGAAUGAGCCUCGAUAACUCUUA 173AbUUAUCGAGGCUCAUUCUCAUUAb 362 UAUGAGAAUGAGCCUCGAUAACUCUU 174UAUAUAAUUAUCGAGGCUCAUUCUCAAb 363 TGGAGAAUGAGCCUCGAUAACUCUUA 175GGCAGCCCCUUAUUGUUAUACGATT 364 GUGGAGAAUGAGCCUCGAUAACUCUU 176GGCAGCCCCUUAUUGUUAUACGAUUT 365 UGAGAAUGAGCCUCGAUAAUU 177CAGCCCCUUAUUGUUAUACGATTTT 366 TCGUAUAACAAUAAGGGGCUU 178GCGAUAGUUAUCGAGGCUCAUUCUCA 367 UGAGAAUGAGCCUCGAUAAUUAUAUA 179UGAAUAGUUAUCGAGGCUCAUUCUCA 368 UCGUAUAACAAUAAGGGGCUGCC 180AUCGUAGUUAUCGAGGCUCAUUCUCA 369 TUCGUAUAACAAUAAGGGGCUGCC 181UAUAAAGUUAUCGAGGCUCAUUCUCA 370 TUCGUAUAACAAUAAGGGGCUG 182AGCCCCUUAUUGUUAUACGAAb 371 UGAGAAUGAGCCUCGAUAACUAUCGC 183AAGCCCCUUAUUGUUAUACGAAb 372 UGAGAAUGAGCCUCGAUAACUAUUCA 184GCAGCCCCUUAUUGUUAUACGAAb 373 UGAGAAUGAGCCUCGAUAACUACGAU 185UAUAUAGUUAUCGAGGCUCAUUCUCAAb 374 UCGUAUAACAAUAAGGGGCGU 186ACGCCCCUUAUUGUUAUACGAAb 375 UCGUAUAACAAUAAGGGGCUGCCU 187GCCCCUUAUUGUUAUACGAUUAb 376 UCGUAUAACAAUAAGGGGCUG 188AGCCCCUUAUUGUUAUACGAUUAb 377 TCGUAUAACAAUAAGGGGCUGCUU 189AAGCCCCUUAUUGUUAUACGAUUAb 378 TCGUAUAACAAUAAGGGGC 1242UAUCAGCCCCUUAUUGUUAUACGA 379 UCGUAUAACAAUAAGGGG 1244UAGCAGCCCCUUAUUGUUAUACGA 380 UCGUAUAACAAUAAGGG 1246GCAGCCCCUUAUUGUUAUACGA 381 TGAGAAUGAGCCUCGAUAA 1248AUAAGAGUUAUCGAGGCUCAUUCUCA 382 UGAGAAUGAGCCUCGAUA 1250AUAGGCAGCCCCUUAUUGUUAUACGA 383 UGAGAAUGAGCCUCGAU 1252CAGCCCCUUAUUGUUAUACGA 384 UGUAUAACAAUAAGGGG 1254UAUAUCAGCCCCTUAUUGUUAUACGA 385 CGUAUAACAAUAAGGGGC 1280AbGCCCCTUAUUGUUAUACGAUUAb 1241 GAGAAUGAGCCUCGAUAA 1281GCCCCUUAUUGUUAUACGA 1243 UCGUAUAACAAUAAGGGGC 1282 CCCCUUAUUGUUAUACGA1245 UGAGAAUGAGCCUCGAUAA 1283 CCCUUAUUGUUAUACGA 1247 UUAUCGAGGCUCAUUCUCA1249 UAUCGAGGCUCAUUCUCA 1251 AUCGAGGCUCAUUCUCA 1253 CCCCUUAUUGUUAUACA1255 UUAUCGAGGCUCAUUCUCA 1258 GCCCCUUAUUGUUAUACGA 1259ACAGCCCCUUAUUGUUAUACGA 1260 AAAGCCCCUUAUUGUUAUACGA 1261GCCCCUUAUUGUUAUACG 1284 UUAUCGAGGCUCAUUCUC 1285 Ab = abasic nucleotide

The LPA RNAi agents described herein are formed by annealing anantisense strand with a sense strand. A sense strand containing asequence listed in Table 1 or Table 2B can be hybridized to anyantisense strand containing a sequence listed in Table 1 or Table 2Aprovided the two sequences have a region of at least 90% complementarityover a contiguous 16, 17, 18, 19, 20, or 21 nucleotide sequence.

In some embodiments, an LPA RNAi agent antisense strand comprises anucleotide sequence of any of the sequences in Table 1. In someembodiments, an LPA RNAi agent antisense strand comprises the sequenceof nucleotides 1-17, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21,2-21, 1-22, 2-22, 1-23, 2-23, 1-24, 2-24, 1-25, 2-25, 1-26, or 2-26 ofany of the sequences in Table 1. In some embodiments, an LPA RNAi agentsense strand comprises the nucleotide sequence of any of the sequencesin Tables 1. In some embodiments, an LPA RNAi agent sense strandcomprises the sequence of nucleotides 1-17, 2-17, 1-18, 2-18, 1-19,2-19, 1-20, 2-20, 1-21, 2-21, 1-22, 2-22, 1-23, 2-23, 1-24, 2-24, 1-25,2-25, 1-26, or 2-26 of any of the sequences in Table 1.

In some embodiments, the sense and antisense strands of the RNAi agentsdescribed herein contain the same number of nucleotides. In someembodiments the sense and antisense strands of the RNAi agents describedherein contain different numbers of nucleotides. In some embodiments,the sense strand 5′ end and the antisense strand 3′ end of an RNAi agentform a blunt end. In some embodiments, the sense strand 3′ end and theantisense strand 5′ end of an RNAi agent form a blunt end. In someembodiments, both ends of an RNAi agent form blunt ends. In someembodiments, neither end of an RNAi agent is blunt-ended. As used hereina blunt end refers to an end of a double stranded RNAi agent in whichthe terminal nucleotides of the two annealed strands are complementary(form a complementary base-pair). In some embodiments, the sense strand5′ end and the antisense strand 3′ end of an RNAi agent form a frayedend. In some embodiments, the sense strand 3′ end and the antisensestrand 5′ end of an RNAi agent form a frayed end. In some embodiments,both ends of an RNAi agent form a frayed end. In some embodiments,neither end of an RNAi agent is a frayed end. As used herein a frayedend refers to an end of a double stranded RNAi agent in which theterminal nucleotides of the two annealed strands from a pair (i.e. donot form an overhang) but are not complementary (i.e. form anon-complementary pair). As used herein, an overhang is a stretch of oneor more unpaired nucleotides at the end of one strand of a doublestranded RNAi agent. The unpaired nucleotides may be on the sense strandor the antisense strand, creating either 3′ or 5′ overhangs. In someembodiments the RNAi agent contains: a blunt end and a frayed end, ablunt end and 5′ overhang end, a blunt end and a 3′ overhang end, afrayed end and a 5′ overhang end, a frayed end and a 3′ overhang end,two 5′ overhang ends, two 3′ overhang ends, a 5′ overhang end and a 3′overhang end, two frayed ends, or two blunt ends.

A nucleotide base (or nucleobase) is a heterocyclic pyrimidine or purinecompound which is a constituent of all nucleic acids and includesadenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U). Asused herein, the term “nucleotide” can include a modified nucleotide ornucleotide mimic, abasic site (Ab or X), or a surrogate replacementmoiety.

In some embodiments, an LPA RNAi agent is prepared or provided as asalt, mixed salt, or a free-acid.

Modified Nucleotides

In some embodiments, an LPA RNAi agent contains one or more modifiednucleotides. As used herein, a “modified nucleotide” is a nucleotideother than a ribonucleotide (2′-hydroxyl nucleotide). In someembodiments, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, or 100% of the nucleotides are modified.Modified nucleotides include, but are not limited to, deoxynucleotides,nucleotide mimics, abasic nucleotides (represented herein as X, Ab),2′-modified nucleotides, 3′ to 3′ linkages (inverted) nucleotides(represented herein as invdN, invN, invn, invX, invAb, non-naturalbase-comprising nucleotides, bridged nucleotides, peptide nucleic acids(PNAs), 2′,3′-seco nucleotide mimics (unlocked nucleobase analogues,represented herein as N_(UNA or) NUNA), locked nucleotides (representedherein as N_(LNA) or NLNA), 3′-O-Methoxy (2′ internucleoside linked)nucleotides (represented herein as 3′-OMen), 2′-F-Arabino nucleotides(represented herein as NfANA or Nf_(ANA)), 5′-Me, 2′-fluoro nucleotide(represented herein as 5Me-Nf), morpholino nucleotides, vinylphosphonate deoxyribonucleotides (represented herein as vpdN), vinylphosphonate containing nucleotides, and cyclopropyl phosphonatecontaining nucleotides (cPrpN). 2′-modified nucleotides (i.e. anucleotide with a group other than a hydroxyl group at the 2′ positionof the five-membered sugar ring) include, but are not limited to,2′-O-methyl nucleotides (represented herein as a lower case letter ‘n’in a nucleotide sequence), 2′-deoxy-2′-fluoro nucleotides (representedherein as Nf, also represented herein as 2′-fluoro nucleotide), 2′-deoxynucleotides (represented herein as dN), 2′-methoxyethyl(2′-O-2-methoxylethyl) nucleotides (represented herein as NM or 2′-MOE),2′-amino nucleotides, and 2′-alkyl nucleotides. It is not necessary forall positions in a given compound to be uniformly modified. Conversely,more than one modification may be incorporated in a single LPA RNAiagent or even in a single nucleotide thereof. The LPA RNAi agent sensestrands and antisense strands may be synthesized and/or modified bymethods known in the art. Modification at one nucleotide is independentof modification at another nucleotide.

Modified nucleotides also include nucleotides having modifiednucleobases. Modified nucleobases include, but are not limited to,synthetic and natural nucleobases, 5-substituted pyrimidines,6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine,5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine,hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives ofadenine and guanine, 2-propyl and other alkyl derivatives of adenine andguanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouraciland cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine andthymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino,8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines andguanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other5-substituted uracils and cytosines, 7-methylguanine and7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and7-deazaadenine and 3-deazaguanine and 3-deazaadenine.

Modified Internucleoside Linkages

In some embodiments, one or more nucleotides of an LPA RNAi agent arelinked by non-standard linkages or backbones (i.e. modifiedinternucleoside linkages or modified backbones). In some embodiments, amodified internucleoside linkage is a non-phosphate-containing covalentinternucleoside linkage. Modified internucleoside linkages or backbonesinclude, but are not limited to, 5′-phosphorothioate group (representedherein as a lower case ‘s’ before a nucleotide, as in sN, sn, sNf, orsdN), chiral phosphorothioates, thiophosphate, phosphorodithioates,phosphotriesters, aminoalkyl-phosphotriesters, methyl and other alkylphosphonates including 3′-alkylene phosphonates and chiral phosphonates,phosphinates, phosphoramidates including 3′-amino phosphoramidate andaminoalkylphosphoramidates, thionophosphoramidates,thionoalkyl-phosphonates, thionoalkylphosphotriesters, morpholinolinkages, and boranophosphates having normal 3′-5′ linkages, 2′-5′linked analogs of these, and those having inverted polarity wherein theadjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to5′-2′. In other embodiments, a modified internucleoside linkage orbackbone lacks a phosphorus atom. Modified internucleoside linkageslacking a phosphorus atom include, but are not limited to, short chainalkyl or cycloalkyl inter-sugar linkages, mixed heteroatom and alkyl orcycloalkyl inter-sugar linkages, or one or more short chain heteroatomicor heterocyclic inter-sugar linkages. In some embodiments, modifiedinternucleoside backbones include, but are not limited to, siloxanebackbones, sulfide, sulfoxide and sulfone backbones; formacetyl andthioformacetyl backbones, methylene formacetyl and thioformacetylbackbones, alkene containing backbones, sulfamate backbones,methyleneimino and methylenehydrazino backbones, sulfonate andsulfonamide backbones, amide backbones; and others having mixed N, O, S,and CH₂ component parts.

In some embodiments, a sense strand of an LPA RNAi agent can contain 1,2, 3, 4 phosphorothioate linkages, an antisense strand of an LPA RNAiagent can contain 1, 2, 3, or 4 phosphorothioate linkages, or both thesense strand and the antisense strand independently can contain 1, 2, 3,or 4 phosphorothioate linkages.

In some embodiments, an LPA RNAi agent sense strand contains twophosphorothioate internucleoside linkages. In some embodiments, the twophosphorothioate internucleoside linkages are between the nucleotides atpositions 1-3 from the 3′ end of the sense strand. In some embodiments,the two phosphorothioate internucleoside linkages are between thenucleotides at positions 1-3, 2-4, 3-5, 4-6, 4-5, or 6-8 from the 5′ endof the sense strand. In some embodiments, an LPA RNAi agent antisensestrand contains four phosphorothioate internucleoside linkages. In someembodiments, the four phosphorothioate internucleoside linkages arebetween the nucleotides at positions 1-3 from the 5′ end of the sensestrand and between the nucleotides at positions 19-21, 20-22, 21-23,22-24, 23-25, or 24-26 from the 5′ end. In some embodiments, an LPA RNAiagent contains two phosphorothioate internucleoside linkages in thesense strand and four phosphorothioate internucleoside linkages in theantisense strand.

In some embodiments, an LPA RNAi agent contains one or more modifiednucleotides and one or more modified internucleoside linkages. In someembodiments, a 2′-modified nucleotide is combined with modifiedinternucleoside linkage.

LPA RNAi Agents Having Modified Nucleotides

Examples of antisense strands containing modified nucleotides areprovided in Table 2A. Examples of sense strands containing modifiednucleotides are provided in Table 2B. In Tables 2A and 2B, the followingnotations are used to indicate modified nucleotides:

-   -   N=2′-OH (unmodified) ribonucleotide (capital letter without for        d indication)    -   n=2′-OMe modified nucleotide    -   Nf=2′-fluoro modified nucleotide    -   dN=2′-deoxy nucleotides    -   N_(UNA)=2′,3′-seco nucleotide mimics (unlocked nucleobase        analogs)    -   N_(LNA)=locked nucleotide    -   Nf_(ANA)=2′-F-Arabino nucleotide    -   NM=2′-methoxyethyl nucleotide    -   Ab=abasic ribose    -   (invdN)=inverted deoxyribonucleotide (3′-3′ linked nucleotide)    -   (invAb)=inverted abasic nucleotide    -   (invn)=inverted 2′-OMe nucleotide    -   s=phosphorothioate linked nucleotide    -   p=phosphate    -   vpdN=vinyl phosphonate deoxyribonucleotide    -   (3′OMen)=3′-OMe nucleotide    -   (5Me-Nf)=5′-Me, 2′-fluoro nucleotide    -   cPrp=cyclopropyl phosphonate    -   epTcPr=see Table 4    -   epTM=see Table 4

In addition the following targeting groups and linking groups are listedin Tables 2A and 2B: (Alk-PEG5-C6), (C11-PEG3-NAG3), (C12),(C6-PEG4-NAG3), (C6-SS-Alk-Me), (Chol-TEG), (Dy540), (NAG13), (NAG18),(NAG24), (NAG25), (NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG31),(NAG32), (NAG33), (NAG34), (NAG35), (NAG36), (NAG37), (NAG4), (PAZ),(Sp18), (Steryl), (Alk-SMPT-C6). Each sense strand and/or antisensestrand can have any of the above indicated targeting groups or linkinggroups, as well as other targeting or linking groups, conjugated to the5′ and or 3′ end of the sequence. The chemical structures for thesegroups are provided in Table 4.

TABLE 2A LPA RNAi agent antisense strands having modified nucleotides.Antisense SEQ SEQ Strand ID Antisense strand sequence 5′ → 3′ ID NO.ID NO. AM01240-AS dTCfgGfcAfgUfcCfcUfuCfuGfcGfudTsdT 386 1 AM01241-ASdTGfuAfgCfaCfuCfcUfgCfaCfcCfcdTsdT 387 2 AM01242-ASdTAfaUfaAfgGfgGfcUfgCfcAfcAfgdTsdT 388 3 AM01243-ASdTUfaAfcAfaUfaAfgGfgGfcUfgCfcdTsdT 389 4 AM01244-ASdTGfuAfuAfaCfaAfuAfaGfgGfgCfudTsdT 390 5 AM01245-ASdTCfgUfaUfaAfcAfaUfaAfgGfgGfcdTsdT 391 6 AM01246-ASdTCfgUfcUfgAfgCfaUfuGfuGfuCfadTsdT 392 7 AM01247-ASdTGfcGfuCfuGfaGfcAfuUfgUfgUfcdTsdT 393 8 AM0124S-ASdTUfgCfgUfcUfgAfgCfaUfuGfuGfudTsdT 394 9 AMO1249-ASdTUfcUfgCfgUfcUfgAfgCfaUfuGfudTsdT 395 10 AM01250-ASdTGfgAfuCfuGfgAfuUfuCfgGfcAfgdTsdT 396 11 AM01251-ASdTCfaGfgAfuCfuGfgAfuUfuCfgGfcdTsdT 397 12 AM01252-ASdTCfaUfcUfgAfgCfaUfcGfuGfuCfadTsdT 398 13 AM01253-ASdTGfcAfuCfuGfaGfcAfuCfgUfgUfcdTsdT 399 14 AM01254-ASdTUfgCfaUfcUfgAfgCfaUfcGfuGfudTsdT 400 15 AM01255-ASdTUfcUfgCfaUfcUfgAfgCfaUfcGfudTsdT 401 16 AM01256-ASdTAfaAfgCfcUfcUfaGfgCfuUfgGfadTsdT 402 17 AM01257-ASdTGfuAfcCfcCfgGfgGfgUfuUfcCfudTsdT 403 18 AM01258-ASdTUfgUfaCfcCfcGfgGfgGfuUfuCfcdTsdT 404 19 AM01259-ASdTCfuGfuAfcCfcCfgGfgGfgUtuUfcdTsdT 405 20 AM01260-ASdTUfcCfaUfaAfuGfgUfaGfuAfgCfadTsdT 406 21 AM01261-ASdTGfuCfcAfuAfaUfgGfuAfgUfaGfcdTsdT 407 22 AM01262-ASdTCfuCfuGfuCfcAfuAfaUfgGfuAfgdTsdT 408 23 AM01263-ASdTCfgAfcUfaUfgCfuGfgUfgUfgGfudTsdT 409 24 AM01264-ASdTCfcGfaCfuAfuGfcUfgGfuGfuGfgdTsdT 410 25 AM01265-ASdTUfcCfgAfcUfaUfgCfuGfgUfgUfgdTsdT 411 26 AM01266-ASdTGfgUfcCfgAfcUfaUfgCfuGfgUfgdTsdT 412 27 AM01267-ASdTUfuUfcUfgGfgGfuCfcGfaCfuAfudTsdT 413 28 AM01268-ASdTUfuUfuCfuGfgGfgUfcCfgAfcUfadfsdT 414 29 AM01269-ASdTGfcGfaAfuCfuCfaGfcAfuCfuGfgdTsdT 415 30 AMO1270-ASdTCfcAfaGfgGfcGfaAfuCfuCfaGfcdTsdT 416 31 AM01271-ASdTAfcCfaAfgGfgCfgAfaUfcUfcAfgdTsdT 417 32 AM01272-ASdTCfaCfcAfaGfgGfcGfaAfuCfuCfadTsdT 418 33 AM01273-ASdTAfcAfcCfaAfgGfgCfgAfaUfcUfcdTsdT 419 34 AM01274-ASdTCfcUfgAfcAfcUfgGfgAfuCfcAfudTsdT 420 35 AM01275-ASdTUfgCfaAfgGfaCfaCfuUfgAfuUfcdTsdT 421 36 AM01276-ASdTUfuGfcAfaGfgAfcAfcUfuGfaUfudTsdT 422 37 AM01277-ASdTUfuGfcUfcCfgUfuGfgUfgCfuUfcdTsdT 423 38 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AM03301-ASusCfsguauaAfcAfaUfaAfggggcUfgCfscsuAu 638 156 AM03331-ASusGfsaGfaAfuGfaGfcCfuCfgAfuAfasdTsdT 639 157 AM03375-ASusCfsguauaAfcAfauaAfggggcugcscsuAu 640 156 AM03376-ASusCfsguauaacaauaAfggggcugcscsuAu 641 156 AM03377-ASusGfsagaauGfaGfccuCfgauaacucsusuAu 642 153 AM03427-ASdTsGfaGfaAfuGfaGfccuCfgAfuAfaCfuCfuuAu 643 109 AM03486-ASvpdTGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusuAu 644 109 AM03487-ASvpdTsGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusuAu 645 109 AM03488-ASdTsGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusuAu 646 109 AM03490-ASvpdTCfsgUfaUfaAfcAfauaAfgGfgGfcUfgCfscsuAu 647 111 AM03491-ASvpdTsCfsgUfaUfaAfcAfauaAfgGfgGfcUfgCfscsuAu 648 111 AM03655-ASusGfsAfgaaugagccuCfgauaacucsusuAu 649 153 AM03656-ASusGfsaGfaaugagccuCfgauaacucsusuAu 650 153 AM03657-ASusGfsagAfaugagccuCfgauaacucsusuAu 651 153 AM03658-ASusGfsagaAfugagccuCfgauaacucsusuAu 652 153 AM03659-ASusGfsagaaUfgagccuCfgauaacucsusuAu 653 153 AM03660-ASusGfsagaauGfagccuCfgauaacucsusuAu 654 153 AM03661-ASusGfsagaaugaGfccuCfgauaacucsusuAu 655 153 AM03671-ASusCfsgUfaUfaAfcAfauaAfgGfcGfcUfgCfscsuAu 656 158 AM03672-ASusCfsgUfaUfaAfcAfauaAfggggCfugCfscsuAu 657 156 AM03673-ASusCfsgUfaUfaAfcAfauaAfggggcugcscsuAu 658 156 AM03674-ASusCfsGfuauaAfcAfauaAfggggcugcscsuAu 659 156 AM03675-ASusCfsgUfaUfaAfcaauaAfggggcugcscsuAu 660 156 AM03676-ASusCfsgUfaUfaaCfaauaAfggggcugcscsuAu 661 156 AM03677-ASusCfsGfuauAfaCfaauaAfggggcugcscsuAu 662 156 AM03678-ASusGfsaGfaAfuGfaGfccuCfgauaacucsusuAu 663 153 AM03679-ASusGfsAfgaAfuGfaGfccuCfgauaacucsusuAu 664 153 AM03680-ASusGfsAfgAfauGfaGfcCfuCfgauaacucsusuAu 665 153 AM03681-ASusGfsAfgAfauGfagCfCfuCfgauaacucsusuAu 666 153 AM03682-ASusGfsaGfaAfuGfagccuCfgauaacucsusuAu 667 153 AM03744-ASusGfsuauaaCfaAfuaaGfgggAbAbs(PAZ) 668 135 AM03745-ASusGfsuAfuAfaCfaAfuAfaGfgGMGMAbAbs(PAZ) 669 135 AM03749-ASusCfsguauaAfcAfauaAfgggAbAbs(PAZ) 670 136 AM03750-ASusCfsgUfaUfaAfcAfaUfaAfgGMGMAbAbs(PAZ) 671 136 AM03754-ASusGfsagaauGfaGfccuCfgauAbAbs(PAZ) 672 148 AM0375S-ASusGfsagaaugagcCfuCfgauAbAbs(PAZ) 673 148 AM03756-ASusGfsaGfaAfuGfaGfcCfuCfgAMTMAbAbs(PAZ) 674 159 AM03760-ASusGfsacaccUfgAfuucUfguuAbAbs(PAZ) 675 151 AM03761-ASusGfsaCfaCfcugaUUcUfguuAbAbs(PAZ) 676 151 AM03762-ASusGfsaCfaCfcUfgAfuUfcUfgTMTMAbAbs(PAZ) 677 160 AM03823-ASusCf_(ANA)sgUfaUfaAfCfAfauaAfgGfgGfcUfgcscsuAu 678 156 AM03824-ASusCfsgUf_(ANA)aUfaAfCfAfauaAfgGfgGfcUfgcscsuAu 679 156 AM03825-ASusCfsgUfaUf_(ANA)aAfCfAfauaAfgGfgGfcUfgcscsuAu 680 156 AM03826-ASusCfsgUfaUfaAf_(ANA)CfAfauaAfgGfgGfcUfgcscsuAu 681 156 AM03827-ASusGf_(ANA)sagaauGfaGfccuCfgauaacucsusuAu 682 153 AM03828-ASusGfsagaauGf_(ANA)aGfccuCfgauaacucsusuAu 683 153 AM03856-ASTMsGfsagaauGfaGfccuCfgauaacucsusuAu 684 109 AM03857-ASTMsCfsgUfaUfaAfCfAfauaAfgGfgGfcUfgcscsuAu 685 111 AM03862-ASTMsGfsagaaugagccuCfgauaacucsusuAu 686 109 AM03866-ASusCfsgUfaUfaacaauaAfggggcugcscsuAu 687 156 AM03867-ASusCfsgUfauaAfcaauaAfggggcugcscsuAu 688 156 AM03868-ASusCfsgUfauaacAfauaAfggggcugcscsuAu 689 156 AM03869-ASusCfsgUfauaacaaUfaAfggggcugcscsuAu 690 156 AM03870-ASusCfsguaUfaAfcaauaAfggggcugcscsuAu 691 156 AM03871-ASusCfsguaUfaacAfauaAfggggcugcscsuAu 692 156 AM03872-ASusCfsguaUfaacaaUfaAfggggcugcscsuAu 693 156 AM03873-ASusCfsguauaAfcaaUfaAfggggcugcscsuAu 694 156 AM03874-ASusCfsguauaacAfaUfaAfggggcugcscsuAu 695 156 AM03875-ASusCfsgUfaUfaAfcAfaUfaAfgggGfcUfgCfscsuAu 696 156 AM03876-ASusCfsgUfaUfaAfcAfaUfaAfgGfggcUfgCfscsuAu 697 156 AM03877-ASusCfsgUfaUfaAfcAfaUfaAfgGfgGfcugCfscsuAu 698 156 AM03878-ASusCfsgUfaUfaAfcAfaUfaAfgGfgGfcUfgcscsuAu 699 156 AM03883-ASvpusCfsgsUfaUfaAfCfAfauaAfgGfgGfcUfgasusu 700 161 AM03884-ASvpusCfsgsUfaUfaAfCfAfauaAfgGfgGfcUfgcsusu 701 162 AM03885-ASvpusGfsasgaauGfaGfccuCfgauaacucsusu 702 163 AM03929-ASusCfsguaUfaAfcaauaAfgGfggcugcscsuAu 703 156 AM03930-ASusCfsguaUfaAfCfaauaAfgGfggcugcscsuAu 704 156 AM03932-ASusGfsagaAfuGfagccuCfgAfuaacucsusuAu 705 153 AM03933-ASusGfsagaAfuGfAfgccuCfgAfuaacucsusuAu 706 153 AM03969-ASvpusCfsgUfaUfaAfCfAfauaAfgGfgGfcUfgcscsuAu 707 156 AM03971-ASvpusCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu 708 164 AM03972-ASusCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu 709 164 AM03973-ASU_(UNA)sCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu 710 164 AM04132-ASusGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusuau 711 153 AM04133-ASusGfsagaauGfaGfccuCfgauaacucsusuau 712 153 AM04134-ASusGfsaGfaAfuGfAfGfccuCfgAfuAfaCfucsusuau 713 153 AM04135-ASusGfsagaauGfAfGfccuCfgauaacucsusuau 714 153 AM04136-ASusGfsaGfaAfuGfAfgccuCfgAfuAfaCfucsusuau 715 153 AM04137-ASusGfsagaauGfAfgccuCfgauaacucsusuau 716 153 AM04150-ASusGfsagaauGfaGfccuCfgauaacucsusuau(Dy540) 717 153 AM04215-ASusCfsgUfaUfaaCfaaUfaAfgGfgGfcUfgCfscsuAu 718 156 AM04216-ASusCfsguauaAfcaaUfaAfggggcugCfscsuAu 719 156 AM04217-ASusCfsguauaaCfaaUfaAfggggcugCfscsuAu 720 156 AM04218-ASusCfsguauaaCfaaUfaAfggggCfugCfscsuAu 721 156 AM04219-ASusCfsguaUfaaCfaaUfaAfggggCfugCfscsuAu 722 156 AM04250-ASusGfsuAfuAfaCfaAfuAfaGfgGMGMsAbsAbs(PAZ) 723 135 AM04251-ASusGfsuAfuAfaCfaAfuAfaGfgGMGM(Sp18)s(PAZ) 724 165 AM04252-ASusGfsuAfuAfaCfaAfuAfaGfgGMGM(C12)s(PAZ) 725 165 AM04253-ASusCfsgUfaUfaAfcAfaUfaAfgGMGMsAbsAbs(PAZ) 726 136 AM04254-ASusCfsgUfaUfaAfcAfaUfaAfgGMGM(Sp18)s(PAZ) 727 166 AM04255-ASusCfsgUfaUfaAfcAfaUfaAfgGMGM(C12)s(PAZ) 728 166 AM04256-ASusGfsaGfaAfuGfaGfcCfuCfgAMTMsAbsAbs(PAZ) 729 159 AM04257-ASusGfsaGfaAfuGfaGfcCfuCfgAMTM(Sp18)s(PAZ) 730 167 AM04258-ASusGfsaGfaAfuGfaGfcCfuCfgAMTM(C12)s(PAZ) 731 167 AM04259-ASusGfsaCfaCfcUfgAfuUfcUfgTMTMsAbsAbs(PAZ) 732 160 AM04260-ASusGfsaCfaCfcUfgAfuUfcUfgTMTM(Sp18)s(PAZ) 733 168 AM04261-ASusGfsaCfaCfcUfgAfuUfcUfgTMTM(C12)s(PAZ) 734 168 AM04377-ASdTusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsua 735 169 AM04378-ASuAusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsu 736 170 AM04379-ASdTcsCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsua 737 171 AM04380-AScUcsCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsu 738 172 AM04383-ASdTusCfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusua 739 173 AM04384-ASuAusGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusu 740 174 AM04385-ASdTgsGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusua 741 175 AM04386-ASgUgsGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusu 742 176 AM04387-ASdTusGfsagaauGfaGfccuCfgauaacucsusua 743 173 AM04388-ASuAusGfsagaauGfaGfccuCfgauaacucsusu 744 174 AM04389-ASdTgsGfsagaauGfaGfccuCfgausacucsusua 745 175 AM04390-ASgUgsGfsagaauGfaGfccuCfgauaacucsusu 746 176 AM04413-ASusCfsgsUfaUfaacaaUfaAfgGfgGfcusu 747 164 AM04415-ASusGfsasGfaAfuGfaGfccuCfgAfuAfausu 748 177 AM04437-ASusGfsuAfuAfaCfaAfuAfaGfgGMGMs(C12)s(PAZ) 749 165 AM04438-ASusCfsgUfaUfaAfcAfaUfaAfgGMGMs(C12)s(PAZ) 750 166 AM04439-ASusGfsaGfaAfuGfaGfcCfuCfgAMTMs(C12)s(PAZ) 751 167 AM04440-ASusGfsaCfaCfcUfgAfuUfcUfgTMTMs(C12)s(PAZ) 752 168 AM04501-AScPrpTMsCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu 753 178 AM04507-ASusGfsasGfaAfuGfaGfccuCfgAfuAfausuAUAUA 754 179 AM04539-ASusCfsgUfaUfaacaaUfaAfgGfgGfcUfgsCfscuAu 755 156 AM04540-ASusCfsgUfaUfaacaaUfaAfgGfgGfcUfgsCfcuAu 756 156 AM04541-ASusGfsaGfaAfuGfaGfccuCfgAfuAfaCfuscsuuAu 757 153 AM04542-ASusGfsaGfaAfuGfaGfccuCfgAfuAfaCfuscuuAu 758 153 AM04544-ASusCfsgsUfaUfaAfCfAfauaAfgGfgGfcUfgcsusu 759 162 AM04545-ASusCfsgsUfaUfaAfCfAfauaagGfgGfcusu 760 164 AM04546-ASusCfsgsUfaUfaAfCfAfaUfaagGfgGfcusu 761 164 AM04582-ASusCfsgUfaUfaacaaUfaAfgGfgGfcUfgsCfsc 762 180 AM04583-ASdTusCfsgUfaUfaacaaUfaAfgGfgGfcUfgsCfsc 763 181 AM04584-ASdTusCfsgUfaUfaacaaUfaAfgGfgGfcUfgscsc 764 181 AM04585-ASdTusCfsgsUfaUfaacaaUfaAfgGfgGfcUfgscsc 765 181 AM04586-ASdTusCfsgsUfaUfaacaaUfaAfgGfgGfcUfgcsc 766 181 AM04587-ASdTusCfsgsUfaUfaacaaUfaAfgGfgGfcusg 767 182 AM04609-ASepTcPrsCfsgsUfaUfaAfCfAfauaAfgGfgGfcusu 768 178 AM04610-ASepTMsCfsgsUfaUfaAiCfAfauaAfgGfgGfcusu 769 178 AM04677-ASusGfsaGfaAfuGfaGfccuCfgAfuAfaCfsuscuuAu 770 153 AM04678-ASusGfsaGfaAfuGfaGfccuCfgAfuAfasCfsucuuAu 771 153 AM04679-ASusGfsaGfaAfuGfaGfccuCfgAfuAfaCfuasuscGc 772 183 AM04680-ASusGfsaGfaAfuGfaGfccuCfgAfuAfaCfuasusuCa 773 184 AM04681-ASusGfsaGfaAfuGfaGfccuCfgAfuAfaCfuascsgAu 774 185 AM04733-ASus(5Me-Gf)saGfaAfuGfaGfccuCfgAfuAfaCfucsusuAu 775 153 AM04734-ASusGfsa(5Me-Gf)aAfuGfaGfccuCfgAfuAfaCfucsusuAu 776 153 AM04735-ASusGfsaGfaAfu(5Me-Gf)aGfccuCfgAfuAfaCfucsusuAu 777 153 AM04736-ASusGfsaGfaAfuGfa(5Me-Gf)ccuCfgAfuAfaCfucsusuAu 778 153 AM04805-ASvpusCfsgsUfaUfaAfCfAfauaAfgGfgGfcgsu 779 186 AM04821-ASusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsu 780 187 AM04822-ASusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfsusu 781 162 AM04823-ASvpusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsu 782 187 AM04824-ASvpusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfsusu 783 162 AM04871-ASusGfsaGfaAfuGfAfgccuCfgAfuAfaCfusCfsuuAu 784 153 AM04872-AScPrpusGfsaGfaAfuGfaGfccuCfgAfuAfaCfucsusuAu 785 153 AM04873-AScPrpusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsuAu 786 156 AM04874-ASusCfsgUfaUfaacaaUfaAfgGfgGfcsusu 787 164 AM04S75-AScPrpusCfsgUfaUfaacaaUfaAfgGfgGfcsusu 788 164 AM04876-ASusCfsgUfaUfaacaaUfaAfgGfgGfcsusg 789 188 AM04877-ASusCfsgUfaUfaacaaUfaAfgGfgGfcsUfsg 790 188 AM04878-AScPrpusCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfsusu 791 162 AM04879-ASusGfsaGfaAfuGfaGfcCfuCfgAfuAfaCfucsusuAu 792 153 AM04880-AScPrpusGfsaGfaAfuGfaGfcCfuCfgAfuAfaCfucsusuAu 793 153 AM04969-AScPrpTMsGfsaGfaAfuGfaGfcCfuCfgAfuAfaCfucsusuAu 794 109 AM04970-AScPrpTMsCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfscsuAu 795 111 AM04971-AScPrpTMsCfsgUfaUfaacaaUfaAfgGfgGfcsusu 796 178 AM04972-AScPrpTMsCfsgUfaUfaacaaUfaAfgGfgGfcUfgCfsusu 797 189 AM04979-ASusCfsgsUfaUfaAfcAfaUfaAfgGfgGfcusu 798 164 1532-AS01usgsagaaugaGfccuCfgAfuAfaCfuCfsusuAu 799 153 1532-AS02usgsagaauGfagccuCfgAfuAfaCfuCfsusuAu 800 153 1532-AS03usgsagaAfugagccuCfgAfuAfaCfuCfsusuAu 801 153 1532-AS04usgsaGfaaugagccuCfgAfuAfaCfuCfsusuAu 802 153 1532-AS05usGfsagaaugagccuCfgAfuAfaCfuCfsusuAu 803 153 1532-AS06dTsgsagaaugagccuCfgAfuAfaCfuCfsusuAu 804 109 1532-AS07dTsGfsaGfaAfugagccuCfgAfuAfaCfuCfsusuAu 805 109 1532-AS08dTsGfsaGfaAfugaGfccuCfgauAfaCfuCfsusuAu 806 109 1532-AS09dTsGfsaGfaAfuGfagccuCfgauAfaCfuCfsusuAu 807 109 1532-AS10dTsGfsaGfaAfugagccuCfgauAfaCfuCfsusuAu 808 109 1532-AS11dTsGfsaGfaAfugagccuCfgAfuaaCfuCfsusuAu 809 109 1532-AS12dTsGfsaGfaAfugaGfccuCfgauaaCfuCfsusuAu 810 109 1532-AS13dTsGfsaGfaAfuGfagccuCfgauaaCfuCfsusuAu 811 109 1532-AS15dTsgsagaaugaGfccuCfgAfuAfaCfuCfsusuAu 812 109 1532-AS16dTsgsagaauGfagccuCfgAfuAfaCfuCfsusuAu 813 109 1532-AS17dTsgsagaAfugagccuCfgAfuAfaCfuCfsusuAu 814 109 1532-AS18dTsgsaGfaaugagccuCfgAfuAfaCfuCfsusuAu 815 109 1532-AS19dTsGfsagaaugagccuCfgAfuAfaCfuCfsusuAu 816 109 1532-AS20usgsagaaugagccuCfgAfuAfaCfuCfsusuAu 817 153 1532-AS21usGfsaGfaAfugagccuCfgAfuAfaCfuCfsusuAu 818 153 1532-AS22usGfsaGfaAfugaGfccuCfgauAfaCfuCfsusuAu 819 153 1532-AS23usGfsaGfaAfuGfagccuCfgauAfaCfuCfsusuAu 820 153 1532-AS24usGfsaGfaAfugagccuCfgauAfaCfuCfsusuAu 821 153 1532-AS25usGfsaGfaAfugagccuCfgAfuaaCfuCfsusuAu 822 153 1532-AS27usGfsaGfaAfuGfagccuCfgauaaCfuCfsusuAu 823 153 1533-AS01usgsaCfaCfcugAfuucUfgUfuUfcUfgAfsgsuAu 824 154 1533-AS02usgsaCfaCfcUfgauucUfgUfuUfcUfgAfsgsuAu 825 154 1533-AS04dTsgsaCfaCfcugauucUfgUfuUfcUfgAfsgsuAu 826 110 1533-AS05dTsGfsaCfaCfcugAfuucUfguuUfcUfgAfsgsuAu 827 110 1533-AS06dTsGfsaCfaCfcUfgauucUfguuUfcUfgAfsgsuAu 828 110 1533-AS07dTsGfsaCfaCfcUfgauucUfgUfuucUfgAfsgsuAu 829 110 1533-AS08dTsGfsaCfaCfcUfgAfuucUfguuucUfgAfsgsuAu 830 110 1533-AS09dTsGfsaCfaCfcUfgAfuucUfguuUfcugAfsgsuAu 831 110 1533-AS10dTsGfsaCfaCfcUfgAfuucUfgUfuucugAfsgsuAu 832 110 1533-AS11dTsGfsaCfaCfcUfgAfuucUfguuucugAfsgsuAu 833 110 1533-AS12dTsGfsaCfaCfcUfgAfuucUfguuucUfgasgsuAu 834 110 1533-AS13dTsGfsaCfaCfcUfgAfuucUfguuUfcugasgsuAu 835 110 1533-AS16dTsgsaCfaCfcugAfuucUfgUfuUfcUfgAfsgsuAu 836 110 1533-AS17dTsgsaCfaCfcUfgauucUfgUfuUfcUfgAfsgsuAu 837 110 1533-AS19usgsaCfaCfcugauucUfgUfuUfcUfgAfsgsuAu 838 154 1533-AS20usGfsaCfaCfcugAfuucUfguuUfcUfgAfsgsuAu 839 154 1533-AS21usGfsaCfaCfcUfgauucUfguuUfcUfgAfsgsuAu 840 154 1533-AS22usGfsaCfaCfcUfgauucUfgUfuucUfgAfsgsuAu 841 154 1533-AS23usGfsaCfaCfcUfgAfuucUfguuucUfgAfsgsuAu 842 154 3533-AS24usGfsaCfaCfcUfgAfuucUfguuUfcugAfsgsuAu 843 154 1533-AS25usGfsaCfaCfcUfgAfuucUfgUfuucugAfsgsuAu 844 154 1533-AS26usGfsaCfaCfcUfgAfuucUfguuucugAfsgsuAu 845 154 1533-AS27usGfsaCfaCfcUfgAfuucUfguuucUfgasgsuAu 846 154 1533-AS28usGfsaCfaCfcUfgAfuucUfguuUfcugasgsuAu 847 154 1533-CfinASdTsGfsacaccUfgAfuucUtgUfuUfcUfgAfsgsuAu 848 110 AM05490-ASusGfsasGfaAfuGfaGfcCfuCfgAfuAfausu 1262 177 AM05492-AScPrpTMsCfsgsUfaUfaAfCfAfaUfaAfgGfgGfcusu 1263 178 AM05493-AScPrpTMsCfsgsUfaUfaAfcAfaUfaAfgGfgGfcusu 1264 178 AM05495-ASusCfsguauaaCfaaUfaAfgggGfcugCfscsuAu 1265 156 AM05496-ASusCfsguaUfaaCfasUfaAfgggGfcugCfscsuAu 1266 156 AM0S497-ASusCfsgUfaUfaacaaUfaAfgGfgGfcsUfsu 1267 164 AM0S498-ASusCfsgsUfaUfaAfCfAfaUfaAfgGfgGfcusu 1268 164

TABLE 2B LPA RNAi agent sense strands having modified nucleotides. SenseSEQ SEQ Strand ID SS Sequence 5′ → 3′ ID NO. ID NO. AM01173-SSAfcGfcAfgAfaGfgGfaCfuGfcCfgAf(invdT) 849 190 AM01174-SSGfgGfgUfgCfaGfgAfgUfgCfuAfcAf(invdT) 850 191 AM01175-SSCfuGfuGfgCfaGfcCfccfuUfaUfuAf(invdT) 851 192 AM01176-SSGfgCfaGfcCfcCfuUfaUfuGfuUfaAf(invdT) 852 193 AM01177-SSAfgCfcCfcUfuAfuUfgUfuAfuAfcAf(invdT) 853 194 AM01178-SSGfcCfcCfuUfaUfuGfuUfaUfaCfgAf(invdT) 854 195 AM01179-SSUfgAfcAfcAfaUfgCfuCfaGfaCfgAf(invdT) 855 196 AM01180-SSGfaCfaCfaAfuGfcUfcAfgAfcGfcAf(invdT) 856 197 AM01181-SSAfcAfcAfaUfgCfuCfaGfaCfgCfaAf(invdT) 857 198 AM01182-SSAfcAfaUfgCfuCfaGfaCfgCfaGfaAf(invdT) 858 199 AM01183-SSCfuGfcCfgAfaAfuCfcAfgAfuCfcAf(invdT) 859 200 AM01184-SSGfcCfgAfaAfuCfcAfgAfuCfcUfgAf(invdT) 860 201 AM01185-SSUfgAfcAfcGfaUfgCfuCfaGfaUfgAf(invdT) 861 202 AM01186-SSGfaCfaCfgAfuGfcUfcAfgAfuGfcAf(invdT) 862 203 AM01187-SSAfcAfcGfaUfgCfuCfaGfaUfgCfaAf(invdT) 863 204 AM01188-SSAfcGfaUfgCfuCfaGfaUfgCfaGfaAf(invdT) 864 205 AM01189-SSUfcCfaAfgCfcUfaGfaGfgCfuUfuAf(invdT) 865 206 AM01190-SSAfgGfaAfaCfcCfcCfgGfgGfuAfcAf(invdT) 866 207 AM01191-SSGfgAfaAfcCfcCfcGfgGfgUfaCfaAf(invdT) 867 208 AM01192-SSGfaAfaCfcCfcCfgGfgGfuAfcAfgAf(invdT) 868 209 AM01193-SSUfgCfuAfcUfaCfcAfuUfaUfgGfaAf(invdT) 869 210 AM01194-SSGfcUfaCfuAfcCfaUfuAfuGfgAfcAf(invdT) 870 211 AM01195-SSCfuAfcCfaUfuAfuGfgAfcAfgAfgAf(invdT) 871 212 AM01196-SSAfcCfaCfaCfcAfgCfaUfaGfuCfgAf(invdT) 872 213 AM01197-SSCfcAfcAfcCfaGfcAfuAfgUfcGfgAf(invdT) 873 214 AM01198-SSCfaCfaCfcAfgCfaUfaGfuCfgGfaAf(invdT) 874 215 AM01199-SSCfaCfcAfgCfaUfaGfuCfgGfaCfcAf(invdT) 875 216 AM01200-SSAfuAfgUfcGfgAfcCfcCfaGfaAfaAf(invdT) 876 217 AM01201-SSUfaGfuCfgGfaCfcCfcAfgAfaAfaAf(invdT) 877 218 AM01202-SSCfcAfgAfuGfcUfgAfgAfuUfcGfcAf(invdT) 878 219 AM01203-SSGfcUfgAfgAfuUfcGfcCfcUfuGfgAf(invdT) 879 220 AM01204-SSCfuGfaGfaUfuCfgCfcCfuUfgGfuAf(invdT) 880 221 AM01205-SSUfgAfgAfuUfcGfcCfcUfuGfgUfgAf(invdT) 881 222 AM01206-SSGfaGfaUfuCfgCfcCfuUfgGfuGfuAf(invdT) 882 223 AM01207-SSAfuGfgAfuCfcCfaGfuGfuCfaGfgAf(invdT) 883 224 AM01208-SSGfaAfuCfaAfgUfgUfcCfuUfgCfaAf(invdT) 884 225 AM01209-SSAfaUfcAfaGfuGfuCfcUfuGfcAfaAf(invdT) 885 226 AM01210-SSGfaAfgCfaCfcAfaCfgGfaGfcAfaAf(invdT) 886 227 AM01211-SSGfaGfuUfaUfcGfaGfgCfuCfaUfuAf(invdT) 887 228 AM01212-SSAfgUfuAfuCfgAfgGfcUfcAfuUfcAf(invdT) 888 229 AM01213-SSGfaCfaAfcAfgAfaUfaUfuAfuCfcAf(invdT) 889 230 AM01214-SSCfuUfgGfuGfuUfaUfaCfcAfuGfgAf(invdT) 890 231 AM01215-SSGfgUfgUfuAfuAfcCfaUfgGfaUfcAf(invdT) 891 232 AM01216-SSUfaUfaCfcAfuGfgAfuCfcCfaAfuAf(invdT) 892 233 AM01217-SSAfuAfcCfaUfgGfaUfcCfcAfaUfgAf(invdT) 893 234 AM01218-SSUfaCfcAfuGfgAfuCfcCfaAfuGfuAf(invdT) 894 235 AM01219-SSAfcCfaUfgGfaUfcCfcAfaUfgUfcAf(invdT) 895 236 AM01220-SSGfcAfaCfcUfgAfcAfcAfaUfgUfcAf(invdT) 896 237 AM01221-SSCfuGfaCfaCfaAfuGfuCfcAfgUfgAf(invdT) 897 238 AM01222-SSCfcAfgUfgAfcAfgAfaUfcAfaGfuAf(invdT) 898 239 AM01223-SSUfuAfuCfgAfgGfcUfcAfuUfcUfcAf(invdT) 899 240 AM01224-SSAfgAfaUfaCfuAfcCfcAfaAfuGfgAf(invdT) 900 241 AM01225-SSAfaUfaCfuAfcCfcAfaAfuGfgUfgAf(invdT) 901 242 AM01226-SSAfuAfcUfaCfcCfaAfaUfgGfuGfgAf(invdT) 902 243 AM01227-SSAfuUfcGfcCfcUfuGfgUfgUfuAfuAf(invdT) 903 244 AM01228-SSUfaUfaCfcAfuGfgAfuCfcCfaGfuAf(invdT) 904 245 AM01229-SSAfuAfcCfaUfgGfaUfcCfcAfgUfgAf(invdT) 905 246 AM01230-SSCfaCfaAfcUfcCfcAfcGfgUfgGfuAf(invdT) 906 247 AM01231-SSAfaGfaAfcAfuGfuCfaGfuCfuUfgAf(invdT) 907 248 AM01232-SSAfgUfgUfcCfuCfaCfaAfcUfcCfcAf(invdT) 908 249 AM01233-SSAfaCfaAfgCfaCfcAtcCfuGfaGfaAf(invdT) 909 250 AM01234-SSCfcUfgAfgAfaAfaGfcCfcUfgUfgAf(invdT) 910 251 AM01235-SSUfgAfuAfcCfaCfaCfuGfgCfaUfcAf(invdT) 911 252 AM01236-SSGfaUfaCfcAfcAfcUfgGfcAfuCfaAf(invdT) 912 253 AM01237-SSGfaAfaCfaGfaAfuCfaGfgUfgUfcAf(invdT) 913 254 AM01238-SSAfaAfcAfgAfaUfcAfgGfuGfuCfcAf(invdT) 914 255 AM01239-SSCfaGfaAfuCfaGfgUfgUfcCfuAfgAf(invdT) 915 256 AM01795-SSCfcUfgUfgGfcAfgCfcCfcUfuAfuAf(invdT) 916 257 AM01797-SSUfgGfcAfgCfcCfcUfuAfuUfgUfuAf(invdT) 917 258 AM01799-SSAfcAfcCfaGfcAfuAfgUfcGfgAfcAf(invdT) 918 259 AM01801-SSGfgAfaUfcCfaGfaUfgCfuGfaGfaAf(invdT) 919 260 AM01803-SSUfcCfaGfaUfgCfuGfaGfaUfuCfgAf(invdT) 920 261 AM01805-SSAfuGfcUfgAfgAfuUfcGfcCfcUfuAf(invdT) 921 262 AM01807-SSCfcAfuGfgAfuCfcCfaGfuGfuCfaAf(invdT) 922 263 AM01809-SSCfuGfaAfgAfaGfcAfcCfaAfcGfgAf(invdT) 923 264 AM01811-SSUfcCfaGfuGfaCfaGfaAfuCfaAfgAf(invdT) 924 265 AM01813-SSCfuCfaCfaAfcUfcCfcAfcGfgUfgAf(invdT) 925 266 AM01815-SSAfgAfaUfcAfgGfuGfuCfcUfaGfaAf(invdT) 926 267 AM01817-SSUfcAfgGfuGfuCfcUfaGfaGfaCfuAf(invdT) 927 268 AM02006-SS(Chol-TEG)uAuAfgCfcCfcUfUfAfuUfgUfuAfuAfcAf(invdT) 928 269 AM02010-SS(Chol-TEG)uAuGfcCfcCfuUfAfUfuGfuUfaUfaCfgAf(invdT) 929 270 AM02014-SS(Chol-TEG)uAuGfaCfaCfaAfUfGfcUfcAfgAfcGfcAf(invdT) 930 271 AM02018-SS(Chol-TEG)uAuAfcAfcAfaUfGfCfuCfaGfaCfgCfaAf(invdT) 931 272 AM02022-SS(Chol-TEG)uAuUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(invdT) 932 273 AM02026-SS(Chol-TEG)uAuGfaAraCfaGfAfAfuCfaGfgUfgUfcAf(invdT) 933 274 AM02030-SS(Chol-TEG)uAuAfcAfcCfaGfCfAfuAfgUfcGfgAfcAf(invdT) 934 275 AM02034-SS(Chol-TEG)uAuUfcCfaGfaUfGfCfuGfaGfaUfuCfgAf(invdT) 935 276 AM02038-SS(Chol-TEG)uAuAfuGfcUfgAfgAfuUfcGfcCfcUfuAf(invdT) 936 277 AM02042-SS(Chol-TEG)uAuCfcAfuGfgAfUfCfcCfaGfuGfuCfaAf(invdT) 937 278 AM02211-SSUfgUfgGfcAfGfCfcCfcUfuAfuUfgAf(invdT) 938 279 AM02212-SSCfaCfaAfuGfCfUfcAfgAfcGfcAfgAf(invdT) 939 280 AM02213-SSCfcGfaAfaUfCfCfaGfaUfcCfuGfuAf(invdT) 940 281 AM02214-SSGfaCfuGfaGfGfAfaAfcCfcCfcGfgAf(invdT) 941 282 AM02215-SSCfuAfcUfaCfCfAfuUfaUfgGfaCfaAf(invdT) 942 283 AM02216-SSAfcUfaCfcAfUfUfaUfgGfsCfaGfaAf(invdT) 943 284 AM02217-SSUfaCfcAfuUfAfUfgGfaCfaGfaGfuAf(invdT) 944 285 AM02218-SSAfcCfaUfuAfUfGfgAfcAfgAfgUfuAf(invdT) 945 286 AM02219-SSAfgAfuGfcUfGfAfgAfuUfcGfcCfcAf(invdT) 946 287 AM02220-SSGfaUfgCfuGfAfGfaUfuCfgCfcCfuAf(invdT) 947 288 AM02221-SSAfgAfuUfcGfCfCfcUfuGfgUfgUfuAf(invdT) 948 289 AM02222-SSGfaCfaGfaAfUfCfaAfgUfgUfcCfuAf(invdT) 949 290 AM02223-SSAfcAfuGfuCfAfGfuCfuUfgGfuCfcAf(invdT) 950 291 AM02224-SSCfcAfaAfuGfGfUfgGfcCfuGfaCfcAf(invdT) 951 292 AM02225-SSUfgGfuGfuUfAfUfaCfcAfuGfgAfuAf(invdT) 952 293 AM02226-SSUfgUfuAfuAfCfCfaUfgGfaUfcCfcAf(invdT) 953 294 AM02227-SSAfaCfcUfgAfCfAfcAfaUfgUfcCfaAf(invdT) 954 295 AM02228-SSAfaUfgUfcCfAfGfuGfaCfaGfaAfuAf(invdT) 955 296 AM02229-SSUfgUfuUfcUfGfAfaCfaAfgCfaCfcAf(invdT) 956 297 AM02230-SSUfaUfcGfaGfGfCfuCfaUfuCfuCfcAf(invdT) 957 298 AM02231-SSUfcGfaGfgCfUfCfaUfuCfuCfcAfcAf(invdT) 958 299 AM02232-SSUfcCfuCfaCfAfAfcUfcCfcAfcGfgAf(invdT) 959 300 AM02233-SSCfaAfcUfcCfCfAfcGfgUfgGfuCfcAf(invdT) 960 301 AM02234-SSGfcUfcCfuUfCfUfgAfaCfaAfgCfaAf(invdT) 961 302 AM02235-SSAfuAfcCfaCfAfCfuGfgCfaUfcAfgAf(invdT) 962 303 AM02236-SSAfcAfgAfaUfCfAfgGfuGfuCfcUfaAf(invdT) 963 304 AM02237-SSGfaAfuCfaGfGfUfgUfcCfuAfgAfgAf(invdT) 964 305 AM02238-SSAfaUfcAfgGfUfGfuCfcUfaGfaGfaAf(invdT) 965 306 AM02239-SSAfuCfaGfgUfGfUfcCfuAfgAfgAfcAf(invdT) 966 307 AM02441-SSuAuAusAfsgUfuAfuCfgAfgGfcUfcAfuUfcUfcAf(C6-SS-Alk-Me) 967 308 AM02442-SSuAuAusAfsgUfuAfuCfgaGfGfcUfcAfuUfcUfcAf(C6-SS-Alk-Me) 968 308 AM02443-SSuAuAusAfsgUfuAfuCfGfaGfGfcUfcAfuUfcUfcAf(C6-SS-Alk-Me) 969 308AM02444-SS uAuAusasGfuUfaUfcGfaGfGfcUfcAtuUfcUfcAf(C6-SS-Alk-Me) 970 308AM02445-SS uAuAusCfsaGfaAfaCfaGfaAfuCfaGfgUfgUfcAf(C6-SS-Alk-Me) 971 309AM02446-SS uAuAusCfsaGfaAfaCfagAfAfuCfaGfgUfgUfcAf(C6-SS-Alk-Me) 972 309AM02447-SS uAuAusCfsaGfaAfaCfAfgAfAfuCfaGfgUfgUfcAf(C6-SS-Alk-Me) 973309 AM02448-SS uAuAuscsAfgAfaAfcAfgAfAfuCfaGfgUfgUfcAf(C6-SS-Alk-Me) 974309 AM02537-SS uAuAusCfsaGfcCfcCfuUfAfUfuGfuUfaUfaCfgAf(C11-PEG3-NAG3)975 310 AM02538-SSuAuAusCfsuGfaCfaCfaAfUfGfcUfcAfgAfcGfcAf(C11-PEG3-NAG3) 976 311AM02539-SS uAuAusUfsgAfcAfcAfaUfGfCfuCfaGfaCfgCfaAf(C11-PEG3-NAG3) 977312 AM02540-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(C11-PEG3-NAG3)978 308 AM02541-SSuAuAusCfsaGfaAfaCfaGfAfAfuCfaGfgUfgUfcAf(C11-PEG3-NAG3) 979 309AM02542-SS uAuAusAfsgAfuGfcUfgAfGfAfuUfcGfcCfcUfuAf(C11-PEG3-NAG3) 980313 AM02793-SS gsCfsaGfcCfcCfuUfaUfuGfuUfa(invdA) 981 314 AM02794-SSgsCfscCfcUfuAfuUfgUfuAfuAfc(invdA) 982 315 AM02795-SScsCfscCfuUfaUfuGfuUfaUfaCfg(invdA) 983 316 AM02796-SSasCfsaCfaAfuGfcUfcAfgAfcGfe(invdA) 984 317 AM02797-SScsAfscAfaUfgCfuCfaGfaCfgCfa(invdA) 985 318 AM02798-SScsCfsgAfaAfuCfcAfgAfuCfcUfg(invdA) 986 319 AM02799-SScsAfscGfaUfgCfuCfaGfaUfgCfa(invdA) 987 320 AM02800-SScsCfsaCfaCfcAfgCfaUfaGfuCfg(invdA) 988 321 AM02801-SSusAfsgUfcGfgAfcCfcCfaGfaAfa(invdA) 989 322 AM02802-SScsAfsgAfuGfcUfgAfgAfuUfcGfc(invdA) 990 323 AM02803-SSasAfsuCfaAfgUfgUfcCfuUfgCfa(invdA) 991 324 AM02804-SSasGfsuUfaUfcGfaGfgCfuCfaUfu(invdA) 992 325 AM02805-SSgsUfsuAfuCfgAfgGfcUfcAfuUfc(invdA) 993 326 AM02806-SScsAfsaCfcUfgAfcAfcAfaUfgUfc(invdA) 994 327 AM02807-SSusAfsuCfgAfgGfcUfcAfuUfcUfc(invdA) 995 328 AM02808-SSgsAfsaUfaCfuAfcCfcAfaAfuGfg(invdA) 996 329 AM02809-SSasUfsaCfuAfcCfcAfaAfuGfgUfg(invdA) 997 330 AM02810-SSasAfsaCfaGfaAfuCfaGfgUfgUfc(invdA) 998 331 AM02811-SSasAfscAfgAfaUfcAfgGfuGfuCfc(invdA) 999 332 AM02812-SSCfsasGfcCfcCfuUfaUfuGfuUfa(invdA) 1000 333 AM02813-SSCfscsCfcUfuAfuUfgUfuAfuAfc(invdA) 1001 334 AM02814-SSCfscsCfuUfaUfuGfuUfaUfaCfg(invdA) 1002 335 AM02815-SSCfsasCfaAfuGfcUfcAfgAfcGfc(invdA) 1003 336 AM02816-SSAfscsAfaUfgCfuCfaGfaCfgCfa(invdA) 1004 337 AM02817-SSCfsgsAfaAfuCfcAfgAfuCfcUfg(invdA) 1005 338 AM02818-SSAfscsGfaUfgCfuCfaGfaUfgCfa(invdA) 1006 339 AM02819-SSCfsasCfaCfcAfgCfaUfaGfuCfg(invdA) 1007 340 AM02820-SSAfsgsUfcGfgAfcCfcCfaGfaAfa(invdA) 1008 341 AM02821-SSAfsgsAfuGfcUfgAfgAfuUfcGfc(invdA) 1009 342 AM02822-SSAfsusCfaAfgUfgUfcCfuUfgCfa(invdA) 1010 343 AM02823-SSGfsusUfaUfcGfaGfgCfuCfaUfu(invdA) 1011 344 AM02824-SSUfsusAfuCfgAfgGfcUfcAfuUfc(invdA) 1012 345 AM02825-SSAfsasCfcUfgAfcAfcAfaUfgUfc(invdA) 1013 346 AM02826-SSAfsusCfgAfgGfcUfcAfuUfcUfc(invdA) 1014 347 AM02827-SSAfsasUfaCfuAfcCfcAfaAfuGfg(invdA) 1015 348 AM02828-SSUfsasCfuAfcCfcAfaAfuGfgUfg(invdA) 1016 349 AM02829-SSAfsasCfaGfaAfuCfaGfgUfgUfc(invdA) 1017 350 AM02830-SSAfscsAfgAfaUfcAfgGfuGfuCfc(invdA) 1018 351 AM02861-SSuAuAusAfsgUfuauCfgAfGfGfcUfcAfuUfcUfcAf(C11-PEG3-NAG3) 1019 308AM02941-SS uAuAusasguuaucgAfgGfcucauucuca(C11-PEG3-NAG3) 1020 308AM02942-SS uAuAusasguuaucgaGfGfcucauucuca(C11-PEG3-MAG3) 1021 308AM02946-SS uAuAuscsagaaaCfagAfAfuCfagguguca(C11-PEG3-NAG3) 1022 309AM02947-SS uAuAuscsagaaaCfaGfaAfuCfagguguca(C11-PEG3-NAG3) 1023 309AM02948-SS uAuAuscsagaaacaGfaAfucagguguca(C11-PEG3-NAG3) 1024 309AM02949-SS uAuAuscsagaaacagAfAfucagguguca(C11-PEG3-NAG3) 1025 309AM03030-SS(Stearyl)uAuAusCfsaGfaAfaCfaGfAfAfuCfaGfgUfgUfcAf(C11-PEG3-NAG3) 1026309 AM03036-SS uAuAusCfsagaAfaCfaGfAfAfuCfaGfgUfgUfcAf(C11-PEG3-NAG3)1027 309 AM03037-SSuAuAusCfsagaaaCfaGfAfAfuCfaGfgUfgUfcAf(C11-PEG3-NAG3) 1028 309AM03038-SS uAuAusCfsagaaaCfagaAfuCfaggUfgUfcAf(C11-PEG3-NAG3) 1029 309AM03039-SS uAuAusCfsaGfaAfaCfaGfAfAfuCfagGfuGfucAf(C11-PEG3-NAG3) 1030309 AM03042-SS uAuAusCfsaGfaAfaCfaGfAfAfucagguguca(C11-PEG3-NAG3) 1031309 AM03060-SS uAuAusCfsaGfaAfaCfaGfAfAfuCfaggugUfca(C11-PEG3-NAG3) 1032309 AM03061-SS uAuAusCfsaGraAfaCfaGfAfAfuCfagguguca(C11-PEG3-NAG3) 1033309 AM03062-SS uAuAusCfsagaaaCfaGfAfAfuCfaggugUfca(C11-PEG3-NAG3) 1034309 AM03064-SS uAuAusCfsaGtaAfaCfaGfaAfuCfaGfgugucAf(C11-PEG3-NAG3) 1035309 AM03122-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfCMAM(C11-PEG3-NAG3)1036 308 AM03123-SSuAuAU_(UNA)AfsgsUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(C11-PEG3-NAG3) 1037 308AM03124-SS uAuAuAfsgsUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(C11-PEG3-NAG3) 1038308 AM03125-SS uAuAusCfsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga(C11-PEG3-NAG3)1039 310 AM03126-SSuAuAuscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfgAf(C11-PEG3-NAG3) 1040 310AM03128-SS uAuAuscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga(C11-PEG3-NAG3) 1041310 AM03144-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(C6-PEG4-NAG3)1042 308 AM03220-SS uAuAusAfsgUfuAfuCfgAfGfGfcUfcauucuca 1043 3081532-SS01 AM03221-SS uAuAusAfsgUfuAfuCfgAfGfGfcucauucuca 1044 308AM03222-SS uAuAusAfsguuauCfgAfGfGfcUfcauucuca 1045 308 AM03223-SSuAuAusAfsguuauCfgAfGfGfcucauucuca 1046 308 AM03224-SSuAuAusasguuauCfgAfGfGfcucauucuca 1047 308 AM03225-SSuAuAusasguuaucgAfGfGfcucauucuca 1048 308 AM03226-SSuAuAusAfsgUfuAfuCfgAfGfdGcUfcauucuca 1049 308 AM03227-SSuAuAusAfsgUfuAfuCfgAfGfdGcucauucuca 1050 308 AM03228-SSuAuAusAfsguuauCfgAfGfdGcUfcauucuca 1051 308 AM03229-SSuAuAusAfsguuauCfgAfGfdGcucauucuca 1052 308 AM03230-SSuAuAusasguuauCfgAfGfdGcucauucuca 1053 308 AM03231-SSuAuAusasguuaucgAfGfdGcucauucuca 1054 308 AM03232-SSuAuAusAfsgUfuAfuCfgaGfGfcUfcauucuca 1055 308 AM03233-SSuAuAusAfsgUfuAfuCfgaGfGfcucauucuca 1056 308 AM03234-SSuAuAusAfsguuauCfgaGfGfcUfcauucuca 1057 308 AM03235-SSuAuAusAfsguuauCfgaGfGfcucauucuca 1058 308 AM03236-SSuAuAusasguuauCfgaGfGfcucauucuca 1059 308 AM03237-SSuAuAusasguuaucgaGfGfcucauucuca 1060 308 AM03238-SSuAuAusAfsgUfuAfuCfgAfGfGfcUfcauucuca(C11-PEG3-NAG3) 1061 308 AM03240-SSuAuAusAfsguuauCfgAfGfGfcUfcauucuca(C11-PEG3-NAG3) 1062 308 AM03330-SSuAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf 1063 308 1532-SS00 AM03291-SSuAuAusCfsaGfcCfcCfuUfAfUfuGfuUfaUfaCfgAf 1064 310 AM03292-SSuAuAusCfsagcCfcCfuUfaUfuguUfaUfaCfga 1065 310 AM03293-SSuAuAusCfsagcCfcCfuUfaUfuguuauaCfga 1066 310 AM03294-SSuAuAuscsagccccuUfaUfuguuauacga 1067 310 AM03295-SSuAuAuscsagccccuuAfUfuguuauacga 1068 310 AM03296-SSuAuAusCfsagcCfcCfuUfAfUfuguUfaUfaCfga 1069 310 AM03297-SSuAuAusCfsagcCfcCfuUfAfUfuguuauaCfga 1070 310 AM03298-SSuAuAuscsagccccuUfAfUfuguuauacga 1071 310 AM03299-SSuAuAusCfsagcCfcCfuuAfUfuguuauaCfga 1072 310 AM03277-SSuAuAuscsagccccuUfaUfUguuauacga(C11-PEG3-NAG3) 1073 310 AM03275-SSuAuAusCfsagcCfcCfuUfaUfuguUfaUfaCfga(C11-PEG3-NAG3) 1074 310 AM03276-SSuAuAusCfsagcCfcCfuUfaUfuguuauaCfga(C11-PEG3-NAG3) 1075 310 AM03278-SSuAuAuscsagccccuuAfUfuguuauacga(C11-PEG3-NAG3) 1076 310 AM03287-SSuAuAusCfsagcCfcCfuUfAfUfuguUfaUfaCfga(C11-PEG3-NAG3) 1077 310 AM03288-SSuAuAusCfsagcCfcCfuUfAfUfuguuauaCfga(C11-PEG3-NAG3) 1078 310 AM03289-SSuAuAuscsagccccuUfAfUfuguuauacga(C11-PEG3-NAG3) 1079 310 AM03290-SSuAuAusCfsagcCfcCfuuAfUfuguuauaCfga(C11-PEG3-NAG3) 1080 310 AM03243-SSuAuAusasguuaucgAfGtGfcucauucuca(C11-PEG3-NAG3) 1081 308 AM03424-SS(Chol-TEG)uAuAusasguuaucgaGfGfcucauucuc(invdA) 1082 308 AM03425-SS(Chol-TEG)uAuAusasguuaucgaGfGfcucauucuca 1083 308 AM03426-SS(Chol-TEG)uAuAusAfgUfuAfuCfgAfGfGfcUfcAfuUfcUfc(invdA) 1084 308AM03457-SS CfscsCfcUfuAfuUfgUfuAfuAfca(NAG13) 1085 334 AM03458-SSCfscsCfuUfaUfuGfuUfaUfaCfga(NAG13) 1086 335 AM03459-SSAfsgsAfuGfcUfgAfgAfuUfcGfca(NAG13) 1087 342 AM03460-SSGfsusUfaUfcGfaGfgCfuCfaUfua(NAG13) 1088 344 AM03461-SSAfsusCfgAfgGfcUfcAfuUfcUfca(NAG13) 1089 347 AM03462-SSAfsasCfaGfaAfuCfaGfgUfgUfca(NAG13) 1090 350 AM03489-SSuAuAusasguuaucgaGfGfcucauucuca(NAG13) 1091 308 AM03492-SSuAuAusCfsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga(NAG13) 1092 310 AM03544-SSuAuAuscsagcccCfuUfaUfuguuauacga(NAG13) 1093 310 AM03545-SSuAuAuscsagccccuuAfUfuGfuuauacga(NAG13) 1094 310 AM03546-SSuAuAuscsagccccuUfAfUfuguuauacga(NAG13) 1095 310 AM03547-SSuAuAusAfsgUfuAfuCfgAfGfGfcUfcAfuUfcUfcAf(NAG13) 1096 308 AM03650-SSuAuAusasguuaucgAfGfGfcucauucuca(NAG13) 1097 308 AM03651-SSuAuAuscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga(NAG13) 1098 310 AM03670-SSuAuAuscsagcgccuUfAfUfuguuauacga(NAG13) 1099 352 AM03683-SSuAuAuscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfga 1100 310 AM03741-SScscsccUfUfAfuuguuauaca(NAG13) 1101 334 AM03742-SScscsccUfUfAfuuguuauaCMAM(NAG13) 1102 334 AM03743-SSCMsCMsccUfUfAfuuguuauaCMAM(NAG13) 1103 334 AM03746-SScscscuUfAfUfuguuauacga(NAG13) 1104 335 AM03747-SScscscuUfAfUfuguuauacGMAM(NAG13) 1105 335 AM03748-SSCMsCMscuUfAfUfuguuauacGMAM(NAG13) 1106 335 AM03751-SSasuscgAfGfGfcucauucuca(NAG13) 1107 347 AM03752-SSasuscgAfGfGfcucauucuCMAM(NAG13) 1108 347 AM03753-SSAMsTMscgAfGfGfcucauucuCMAM(NAG13) 1109 353 AM03757-SSasascaGfAfAfucagguguca(NAG13) 1110 350 AM03758-SSasascaGfAfAfucagguguCMAM(NAG13) 1111 350 AM03759-SSAMsAMscaGfAfAfucagguguCMAM(NAG13) 1112 350 AM03859-SS(NAG18)uauausasguuaucgAfGfGfcucauucuc(invdA) 1113 308 AM03861-SS(NAG18)uauauscsaGfcCfcCfuUfAfUfuGfuUfaUfaCfg(invdA) 1114 310 AM03879-SS(NAG4)uscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1115 354 AM03880-SS(NAG4)uscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1116 355 AM03881-SS(NAG24)uscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1117 354 AM03882-SS(NAG4)usaguuaucgAfGfGfcucauucucausu(invAb) 1118 356 AM03928-SSuAuAuscsagcccCfuUfAfUfuguuauacga(NAG13) 1119 310 AM03931-SSuAuAusasguuauCfgAfGfGfcucauucuca(NAG13) 1120 308 AM03968-SS(NAG4)uauauscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgs(invdA) 1121 310 AM03970-SS(NAG4)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1122 357 AM04138-SS(NAG25)uauausasguuaucgAfGfGfcucauucuc(invdA) 1123 308 AM04152-SS(Alk-PEG5-C6)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1124 308 AM04214-SS(Alk-SMPT-C6)uauausaSguuauCgAfGfGfcucauuCuCM(invdA) 1125 308 AM04233-SS(NAG26)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1126 308 AM04372-SS(NAG27)uauausasguuaucgAfGfGfcucauucuCM(invdA) 1127 308 AM04381-SS(NAG25)auauscsagccccuUfAfUfuguuauacga(invdT) 1128 358 AM04382-SS(NAG25)uauscsagccccuUfAfUfuguuauacgau(invdT) 1129 359 AM04391-SS(NAG25)auausasguuaucgAfGfGfcucauucuca(invdT) 1130 360 AM04392-SS(NAG25)uausasguuaucgAfGfGfcucauucucau(invdT) 1131 361 AM04412-SS(NAG25)uauauscsagccccuUfAfUfuguuauacg(invdA) 1132 310 AM04414-SS(NAG25)(invAb)gccccuUfAfUfuguuauacgauus(invAb) 1133 357 AM04416-SS(NAG25)(invAb)uuaucgAfGfGfcucauucucausu(invAb) 1134 362 AM04496-SS(NAG25)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1135 357AM04497-SS (NAG29)uauausasguuaucgAfGfGfcucauucuc(invdA) 1136 308AM04499-SS (NAG28)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(mvAb) 1137 357AM04498-SS (NAG29)uauauaasuuaucgaGfGfcucauucucsa(invAb) 1138 363AM04500-SS (NAG30)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1139357 AM04502-SS (NAG25)uauauaasuuaucgaGfGfcucauucucsa(invAb) 1140 363AM04535-SS (NAG25)uauaucsasgccccuUfAfUfuguuauacg(invdA) 1141 310AM04536-SS (NAG25)uauaucasgccccuUfAfUfuguuauacg(invdA) 1142 310AM04537-SS (NAG25)uauauasgsuuaucgAfGfGfcucauucuc(invdA) 1143 308AM04538-SS (NAG25)uauauagsuuaucgAfGfGfcucauucuc(invdA) 1144 308AM04543-SS (NAG30)uscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1145 355AM04578-SS (NAG25)ggcsagccccuUfAfUfuguuauacgAMs(invdT)dT 1146 364AM04588-SS (NAG25)ggcsagccccuUfAfUfuguuauacgAMsuu(invdT) 1147 365AM04579-SS (NAG25)G_(UNA)gcsagccccuUfAfUfuguuauacgAMs(invdT)dT 1148 364AM04580-SS (NAG25)ggcs(invdA)gccccuUfAfUfuguuauacgAMs(invdT)dT 1149 364AM04581-SS (NAG25)csagccccuUfAfUfuguuauacgAMs(invdT)dTdTdT 1150 366AM04611-SS (NAG31)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1151357 AM04612-SS (NAG32)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb)1152 357 AM04669-SS (NAG25)uauauagsusuaucgAfGfGfcucauucuc(invdA) 1153308 AM04670-SS (NAG25)uauauagususaucgAfGfGfcucauucuc(invdA) 1154 308AM04671-SS (NAG25)gcgausasguuaucgAfGfGfcucauucuc(invdA) 1155 367AM04672-SS (NAG25)ugaausasguuaucgAfGfGfcucauucuc(invdA) 1156 368AM04673-SS (NAG25)aucgusasguuaucgAfGfGfcucauucuc(invdA) 1157 369AM04674-SS (NAG25)u(invdA)uausasguuaucgAfGfGfcucauucuc(invdA) 1158 308AM04675-SS (NAG25)uaua(invdA)sasguuaucgAfGfGfcucauucuc(invdA) 1159 370AM04676-SS (NAG25)uauaus(invdA)sguuaucgAfGfGfcucauucuc(invdA) 1160 308AM04726-SS (NAG30)aGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1161 371AM04727-SS (NAG30)aaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1162 372AM04728-SS (NAG30)sasGfcCfcCfuUtAfUfuGfuUfaUfaCfgas(invAb) 1163 371AM04729-SS (NAG30)gscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1164 373AM04737-SS (NAG25)uauauagsuuaucgaGfGfcucauucucsa(invAb) 1165 374AM04741-SS (NAG30)sgscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1166 373AM04742-SS (NAG33)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1167357 AM04743-SS (NAG34)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb)1168 357 AM04744-SS(NAG35)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1169 357AM04803-SS (NAG30)acGfcCfcCfuUfAfUfuGfuUfaUfaCfgsa(invAb) 1170 375AM04804-SS (NAG30)sasaGfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1171 372AM04807-SS (NAG30)sascGfcCfcCfuUfAfUfuGfuUfaUfsCfgas(invAb) 1172 375AM04806-SS (NAG30)sgscaGfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1173 373AM04808-SS (NAG31)sGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1174 376AM04809-SS (NAG31)saGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1175 377AM04810-SS (NAG31)sasaGfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1176 372AM04811-SS (NAG31)sasaGfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1177 378AM04812-SS (NAG31)sasaGfcCfcCfuUfAfUfuGfuUfaUfaCfg(invdA)usu(invAb) 1178378 AM04813-SS (NAG31)uauausasguuaucgAfGfGfcucauucuc(invdA) 1179 308AM04816-SS (NAG31)uauscsagccccuUfAfUfuguuauacgs(invdA) 1180 379AM04817-SS (NAG31)uagscsagccccuUfAfUfuguuauacgs(invdA) 1181 380AM04835-SS (NAG31)uaucagccccuUfAfUfuguuauacgs(invdA) 1182 372 AM04819-SS(NAG31)sgscagccccuUfAfUfuguuauacgs(invdA) 1183 381 AM04820-SS(NAG31)sgscagccccuUfAfUfuguuauacgsa(invAb) 1184 373 AM04862-SS(NAG25)auaagasguuaucgAfGfGfcucauucuc(invdA) 1185 382 AM04863-SS(NAG25)auaagsasguuaucgAfGfGfcucauucuc(invdA) 1186 382 AM04864-SS(NAG25)auaggcsagccccuUfAfUfuguuauacg(invdA) 1187 383 AM04865-SS(NAG25)auaggscsagccccuUfAfUfuguuauacg(invdA) 1188 383 AM04866-SS(NAG25)scsagccccuUfAfUfuguuauacgs(invdA) 1189 384 AM04867-SS(NAG31)scsagccccuUfAfUfuguuauacgs(invdA) 1190 384 AM04868-SS(NAG25)sgsccccuUfAfUfuguuauacgauus(invAb) 1191 376 AM04869-SS(NAG31)sgsccccuUfAfUfuguuauacgauus(invAb) 1192 376 AM04870-SS(NAG25)sGfsccccuUfAfUfuguuauacgauus(invAb) 1193 376 AM04978-SS(NAG31)sGfscCfcCfuUfAfUfuGfuUfaUfaCfgauus(invAb) 1194 376 AM05070-SS(NAG25)uauauscsagcccc(NOTA-dT)UfAfUfuguuauacg(invdA) 1195 385 AM05072-SS(NAG25)(invAb)GfcCfcCf(NOTA-dT)UfAfUfuGfuUfaUfaCfgausu(invAb) 1196 12411532-SS02 uAuAusAfsgUfuAfuCfgAfGfGfcucAfuucuca 1197 308 1532-SS03uAuAusAfsgUfuAfuCfgAfGfGfcucauUfcuca 1198 308 1532-SS04uAuAusAfsgUfuAfuCfgAfGfGfcucauucUfca 1199 308 1532-SS05uAuAusAfsgUfuAfuCfgAfGfGfcucauucucAf 1200 308 1532-SS06uAuAusAfsgUfuAfuCfgAfgGfcUfcauucucAf 1201 308 1532-SS07uAuAusAfsgUfuAfuCfgAfgGfcucAfuucucAf 1202 308 1532-SS08uAuAusAfsgUfuAfuCfgAfgGfcucauUfcucAf 1203 308 1532-SS09uAuAusAfsgUfuAfuCfgAfgGfcucauucUfcAf 1204 308 1532-SS10uAuAusAfsgUfuAfuCfgAfgGfcucauucucAf 1205 308 1532-SS11uAuAusAfsgUfuAfuCfgaGfGfcucauucucAf 1206 308 1532-SS12uAuAusAfsgUfuAfuCfgagGfcUfcauucucAf 1207 308 1532-SS13uAuAusAfsgUfuAfuCfgagGfcucAfuucucAf 1208 308 1532-SS14uAuAusAfsgUfuAfuCfgagGfcucauUfcucAf 1209 308 1532-SS15uAuAusAfsgUfuAfuCfgagGfcucauucUfcAf 1210 308 1532-SS16uAuAusAfsgUfuAfuCfgagGfcucauUfcUfcAf 1211 308 1532-SS17uAuAusAfsgUfuauCfgAfgGfcucauUfcUfcAf 1212 308 1532-SS18uAuAusAfsgUfuauCfgaGfGfcucauUfcUfcAf 1213 308 1532-SS19uAuAusAfsgUfuauCfgagGfcUfcauUfcUfcAf 1214 308 1532-SS20uAuAusAfsgUfuauCfgagGfcucAfuUfcUfcAf 1215 308 1532-SS21uAuAusAfsgUfuauCfgagGfcUfcAfuUfcUfcAf 1216 308 1532-SS22uAuAusAfsguuAfuCfgagGfcUfcAfuUfcUfcAf 1217 308 1532-SS23uAuAusAfsguuauCfgAfgGfcUfcAfuUfcUfcAf 1218 308 1532-SS24uAuAusAfsguuauCfgaGfGfcUfcAfuUfcUfcAf 1219 308 1533-CfinSSuAuAuscsaGfaAfacaGfAfAfucaGfgUfgUfcAf 1220 309 1533-SS00uAuAusCfsaGfaAfaCfaGfAfAfuCfaGfgUfgUfcAf 1221 309 1533-SS01uAuAusCfsaGfaAfaCfaGfAfAfuCfaGfguguca 1222 309 1533-SS02uAuAusCfsaGfaAfaCfaGfAfAfuCfaggugUfca 1223 309 1533-SS03uAuAusCfsaGfaAfaCfaGfAfAfuCfaggugucAf 1224 309 1533-SS04uAuAusCfsaGfaAfaCfaGfAfAfuCfaggUfguca 1225 309 1533-SS05uAuAusCfsaGfaAfaCfaGfaAfuCfaGfgugucAf 1226 309 1533-SS06uAuAusCfsaGfaAfaCfaGfaAfuCfaggugUfcAf 1227 309 1533-SS07uAuAusCfsaGfaAfaCfaGfaAfuCfaggUfgucAf 1228 309 1533-SS08uAuAusCfsaGfaAfaCfagAfAfuCfaggugUfcAf 1229 309 1533-SS09uAuAusCfsaGfaAfaCfagaAfuCfaggUfgUfcAf 1230 309 1533-SS10uAuAusCfsaGfaAfaCfagaAfuCfaGfgugUfcAf 1231 309 1533-SS11uAuAusCfsaGfaaaCfagAfAfuCfaGfgUfgUfcAf 1232 309 1533-SS20 1533-SS12uAuAusCfsaGfaaaCfaGfaAfuCfaGfgUfgUfcAf 1233 309 1533-SS13uAuAusCfsaGfaAfaCfagaAfuCfaGfgUfgUfcAf 1234 309 1533-SS14uAuAusCfsaGfaaaCfagaAfuCfaGfgUfgUfcAf 1235 309 1533-SS15uAuAusCfsagaAfaCfagaAfuCfaGfgUfgUfcAf 1236 309 1533-SS16uAuAusCfsagaaaCfagAfAfuCfaGfgUfgUfcAf 1237 309 1533-SS17uAuAusCfsagaaaCfaGfaAfuCfaGfgUfgUfcAf 1238 309 1533-SS18uAuAusCfsagaaaCfaGfAfAfuCfaGfgUfgUfcAf 1239 309 1533-SS19uAuAusCfsagaAfaCfagAfAfuCfaGfgUfgUfcAf 1240 309 AM05341-SS(NAG37)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgausu(invAb) 1256 357AM05342-SS (NAG37)scsagccccuUfAfUfuguuauacgs(invdA) 1257 381 AM05489-SS(NAG25)uauausasguuaucgAfGfGfcucauucucas(invAb) 1269 308 AM05491-SS(NAG25)(invAb)uuaucgAfGfGfcucauucucas(invAb) 1270 1258 AM05494-SS(NAG25)(invAb)GfcCfcCfuUfAfUfuGfuUfaUfaCfgas(invAb) 1271 1259 AM05499-SS(NAG25)(invAb)gccccuUfAfUfuguuauacgausu(invAb) 1272 357 AM05500-SS(NAG25)uauauscsagccccuUfAfUfuguuauacgas(invAb) 1273 310 AM05501-SS(NAG25)(invAb)gccccuUfAfUfuguuauacgas(invAb) 1274 1259 AM05502-SS(NAG25)sasagccccuUfAfUfuguuauacgs(invdA) 1275 1261 AM05503-SS(NAG25)scsagccccuUfAfUfuguuauacgas(invAb) 1276 1260 AM05504-SS(NAG25)sgsccccuUfAfUfuguuauacgas(invAb) 1277 371 AM05505-SS(NAG25)sgsccccuUfAfUfuguuauacgs(invdA) 1278 371 AM05506-SS(NAG25)sasagccccuUfAfUfuguuauacgas(invAb) 1279 1261

A sense strand containing a sequence listed in Table 2B can behybridized to any antisense strand containing a sequence listed in Table2A provided the two sequences have a region of at least 90%complementarity over a contiguous 16, 17, 18, 19, 20, or 21 nucleotidesequence. Representative LPA RNAi agents are represented by the DuplexID Nos. shown in Tables 3A and 3B.

In some embodiments an LPA RNAi agent comprises of any of the Duplex IDNos. presented herein. In some embodiments an LPA RNAi agent consists ofany of the Duplex ID Nos. presented herein. In some embodiments, an LPARNAi agent comprises the sense strand and antisense strand nucleotidesequences of any of the Duplex ID Nos. presented herein. In someembodiments, an LPA RNAi agent comprises the sense strand and antisensestrand nucleotide sequences of any of the Duplex ID Nos. presentedherein and a targeting group and/or linking group wherein the targetinggroup and/or linking group is covalently linked (i.e. conjugated) to thesense strand or the antisense strand. In some embodiments, an LPA RNAiagent comprises the sense strand and antisense strand modifiednucleotide sequences of any of the Duplex ID Nos. presented herein. Insome embodiments, an LPA RNAi agent comprises the sense strand andantisense strand modified nucleotide sequences of any of the Duplex IDNos. presented herein and a targeting group and/or linking group whereinthe targeting group and/or linking group is covalently linked to thesense strand or the antisense strand.

TABLE 3A LPA RNAi agent duplexes with Duplex ID numbers. Antisense SenseAntisense Sense Antisense Sense Duplex ID Strand ID Strand ID Duplex IDStrand ID Strand ID Duplex ID Strand ID Strand ID AD00571 AM01240-ASAM01173-SS AD02120 AM03257-AS AM03229-SS AD02500 AM03107-AS AM03295-SSAD00572 AM01241-AS AM01174-SS AD02121 AM03257-AS AM03230-SS AD02501AM03279-AS AM03295-SS AD00573 AM01242-AS AM01175-SS AD02122 AM03257-ASAM03231-SS AD02502 AM03280-AS AM03295-SS AD00574 AM01243-AS AM01176-SSAD02123 AM03257-AS AM03232-SS AD02503 AM03281-AS AM03295-SS AD00575AM01244-AS AM01177-SS AD02124 AM03257-AS AM03233-SS AD02504 AM03282-ASAM03295-SS AD00576 AM01245-AS AM01178-SS AD02125 AM03257-AS AM03234-SSAD02505 AM03283-AS AM03295-SS AD00577 AM01246-AS AM01179-SS AD02126AM03257-AS AM03235-SS AD02506 AM03284-AS AM03295-SS AD00578 AM01247-ASAM01180-SS AD02127 AM03257-AS AM03236-SS AD02507 AM03300-AS AM03295-SSAD00579 AM01248-AS AM01181-SS AD02128 AM03257-AS AM03237-SS AD02508AM03301-AS AM03295-SS AD00580 AM01249-AS AM01182-SS AD02129 AM03258-ASAM03220-SS AD02509 AM03107-AS AM03296-SS AD00581 AM01250-AS AM01183-SSAD02130 AM03258-AS AM03221-SS AD02510 AM03279-AS AM03296-SS AD00582AM01251-AS AM01184-SS AD02131 AM03258-AS AM03222-SS AD02511 AM03280-ASAM03296-SS AD00583 AM01252-AS AM01185-SS AD02132 AM03258-AS AM03223-SSAD02512 AM03281-AS AM03296-SS AD00584 AM01253-AS AM01186-SS AD02133AM03258-AS AM03224-SS AD02513 AM03282-AS AM03296-SS AD00585 AM01254-ASAM01187-SS AD02134 AM03258-AS AM03225-SS AD02514 AM03283-AS AM03296-SSAD00586 AM01255-AS AM01188-SS AD02135 AM03258-AS AM03226-SS AD02515AM03284-AS AM03296-SS AD00587 AM01256-AS AM01189-SS AD02136 AM03258-ASAM03227-SS AD02516 AM03300-AS AM03296-SS AD00588 AM01257-AS AM01190-SSAD02137 AM03258-AS AM03228-SS AD02517 AM03301-AS AM03296-SS AD00589AM01258-AS AM01191-SS AD02138 AM03258-AS AM03229-SS AD02518 AM03107-ASAM03297-SS AD00590 AM01259-AS AM01192-SS AD02139 AM03258-AS AM03230-SSAD02519 AM03279-AS AM03297-SS AD00591 AM01260-AS AM01193-SS AD02140AM03258-AS AM03231-SS AD02520 AM03280-AS AM03297-SS AD00592 AM01261-ASAM01194-SS AD02141 AM03258-AS AM03232-SS AD02521 AM03281-AS AM03297-SSAD00593 AM01262-AS AM01195-SS AD02142 AM03258-AS AM03233-SS AD02522AM03282-AS AM03297-SS AD00594 AM01263-AS AM01196-SS AD02143 AM03258-ASAM03234-SS AD02523 AM03283-AS AM03297-SS AD00595 AM01264-AS AM01197-SSAD02144 AM03258-AS AM03235-SS AD02524 AM03284-AS AM03297-SS AD00596AM01265-AS AM01198-SS AD02145 AM03258-AS AM03236-SS AD02525 AM03300-ASAM03297-SS AD00597 AM01266-AS AM01199-SS AD02146 AM03258-AS AM03237-SSAD02526 AM03301-AS AM03297-SS AD00598 AM01267-AS AM01200-SS AD02147AM03259-AS AM03220-SS AD02527 AM03107-AS AM03298-SS AD00599 AM01268-ASAM01201-SS AD02148 AM03259-AS AM03221-SS AD02528 AM03279-AS AM03298-SSAD00600 AM01269-AS AM01202-SS AD02149 AM03259-AS AM03222-SS AD02529AM03280-AS AM03298-SS AD00601 AM01270-AS AM01203-SS AD02150 AM03259-ASAM03223-SS AD02530 AM03281-AS AM03298-SS AD00602 AM01271-AS AM01204-SSAD02151 AM03259-AS AM03224-SS AD02531 AM03282-AS AM03298-SS AD00603AM01272-AS AM01205-SS AD02152 AM03259-AS AM03225-SS AD02532 AM03283-ASAM03298-SS AD00604 AM01273-AS AM01206-SS AD02153 AM03259-AS AM03226-SSAD02533 AM03284-AS AM03298-SS AD00605 AM01274-AS AM01207-SS AD02154AM03259-AS AM03227-SS AD02534 AM03300-AS AM03298-SS AD00606 AM01275-ASAM01208-SS AD02155 AM03259-AS AM03228-SS AD02535 AM03301-AS AM03298-SSAD00607 AM01276-AS AM01209-SS AD02156 AM03259-AS AM03229-SS AD02536AM03107-AS AM03299-SS AD00608 AM01277-AS AM01210-SS AD02157 AM03259-ASAM03230-SS AD02537 AM03279-AS AM03299-SS AD00609 AM01278-AS AM01211-SSAD02158 AM03259-AS AM03231-SS AD02538 AM03280-AS AM03299-SS AD00610AM01279-AS AM01212-SS AD02159 AM03259-AS AM03232-SS AD02539 AM03281-ASAM03299-SS AD00611 AM01280-AS AM01213-SS AD02160 AM03259-AS AM03233-SSAD02540 AM03282-AS AM03299-SS AD00612 AM01281-AS AM01214-SS AD02161AM03259-AS AM03234-SS AD02541 AM03283-AS AM03299-SS AD00613 AM01282-ASAM01215-SS AD02162 AM03259-AS AM03235-SS AD02542 AM03284-AS AM03299-SSAD00614 AM01283-AS AM01216-SS AD02163 AM03259-AS AM03236-SS AD02543AM03300-AS AM03299-SS AD00615 AM01284-AS AM01217-SS AD02164 AM03259-ASAM03237-SS AD02544 AM03301-AS AM03299-SS AD00616 AM01285-AS AM01218-SSAD02165 AM03260-AS AM03220-SS AD02545 AM03301-AS AM03277-SS AD00617AM01286-AS AM01219-SS AD02166 AM03260-AS AM03221-SS AD02546 AM03107-ASAM03275-SS AD00618 AM01287-AS AM01220-SS AD02167 AM03260-AS AM03222-SSAD02547 AM03107-AS AM03276-SS AD00619 AM01288-AS AM01221-SS AD02168AM03260-AS AM03223-SS AD02548 AM03107-AS AM03277-SS AD00620 AM01289-ASAM01222-SS AD02169 AM03260-AS AM03224-SS AD02549 AM03107-AS AM03278-SSAD00621 AM01290-AS AM01223-SS AD02170 AM03260-AS AM03225-SS AD02550AM03107-AS AM03287-SS AD00622 AM01291-AS AM01224-SS AD02171 AM03260-ASAM03226-SS AD02551 AM03107-AS AM03288-SS AD00623 AM01292-AS AM01225-SSAD02172 AM03260-AS AM03227-SS AD02552 AM03107-AS AM03289-SS AD00624AM01293-AS AM01226-SS AD02173 AM03260-AS AM03228-SS AD02553 AM03107-ASAM03290-SS AD00625 AM01294-AS AM01227-SS AD02174 AM03260-AS AM03229-SSAD02554 AM03279-AS AM02537-SS AD00626 AM01295-AS AM01228-SS AD02175AM03260-AS AM03230-SS AD02555 AM03280-AS AM02537-SS AD00627 AM01296-ASAM01229-SS AD02176 AM03260-AS AM03231-SS AD02556 AM03281-AS AM02537-SSAD00628 AM01297-AS AM01230-SS AD02177 AM03260-AS AM03232-SS AD02557AM03282-AS AM02537-SS AD00629 AM01298-AS AM01231-SS AD02178 AM03260-ASAM03233-SS AD02558 AM03283-AS AM02537-SS AD00630 AM01299-AS AM01232-SSAD02179 AM03260-AS AM03234-SS AD02559 AM03284-AS AM02537-SS AD00631AM01300-AS AM01233-SS AD02180 AM03260-AS AM03235-SS AD02560 AM03300-ASAM02537-SS AD00632 AM01301-AS AM01234-SS AD02181 AM03260-AS AM03236-SSAD02561 AM03301-AS AM02537-SS AD00633 AM01302-AS AM01235-SS AD02182AM03260-AS AM03237-SS AD02609 AM03375-AS AM03277-SS AD00634 AM01303-ASAM01236-SS AD02183 AM03261-AS AM03220-SS AD02610 AM03376-AS AM03277-SSAD00635 AM01304-AS AM01237-SS AD02184 AM03261-AS AM03221-SS AD02611AM03375-AS AM03278-SS AD00636 AM01305-AS AM01238-SS AD02185 AM03261-ASAM03222-SS AD02612 AM03376-AS AM03278-SS AD00637 AM01306-AS AM01239-SSAD02186 AM03261-AS AM03223-SS AD02613 AM03375-AS AM03289-SS AD01068AM01796-AS AM01795-SS AD02187 AM03261-AS AM03224-SS AD02614 AM03376-ASAM03289-SS AD01069 AM01798-AS AM01797-SS AD02188 AM03261-AS AM03225-SSAD02615 AM03377-AS AM02941-SS AD01070 AM01800-AS AM01799-SS AD02189AM03261-AS AM03226-SS AD02616 AM03259-AS AM02941-SS AD01071 AM01802-ASAM01801-SS AD02190 AM03261-AS AM03227-SS AD02617 AM03377-AS AM02942-SSAD01072 AM01804-AS AM01803-SS AD02191 AM03261-AS AM03228-SS AD02618AM03259-AS AM02942-SS AD01073 AM01806-AS AM01805-SS AD02192 AM03261-ASAM03229-SS AD02619 AM03377-AS AM03243-SS AD01074 AM01808-AS AM01807-SSAD02193 AM03261-AS AM03230-SS AD02620 AM03259-AS AM03243-SS AD01075AM01810-AS AM01809-SS AD02194 AM03261-AS AM03231-SS AD02662 AM02860-ASAM03424-SS AD01076 AM01812-AS AM01811-SS AD02195 AM03261-AS AM03232-SSAD02663 AM02860-AS AM03425-SS AD01077 AM01814-AS AM01813-SS AD02196AM03261-AS AM03233-SS AD02664 AM03427-AS AM03426-SS AD01078 AM01816-ASAM01815-SS AD02197 AM03261-AS AM03234-SS AD02682 AM02775-AS AM03457-SSAD01079 AM01818-AS AM01817-SS AD02198 AM03261-AS AM03235-SS AD02683AM02776-AS AM03458-SS AD01184 AM02003-AS AM02006-SS AD02199 AM03261-ASAM03236-SS AD02684 AM02783-AS AM03459-SS AD01185 AM02004-AS AM02006-SSAD02200 AM03261-AS AM03237-SS AD02685 AM02785-AS AM03460-SS AD01186AM02005-AS AM02006-SS AD02201 AM03262-AS AM03220-SS AD02686 AM02788-ASAM03461-SS AD01187 AM02007-AS AM02010-SS AD02202 AM03262-AS AM03221-SSAD02687 AM02791-AS AM03462-SS AD01188 AM02008-AS AM02010-SS AD02203AM03262-AS AM03222-SS AD02696 AM02860-AS AM03243-SS AD01189 AM02009-ASAM02010-SS AD02204 AM03262-AS AM03223-SS AD02697 AM03107-AS AM03277-SSAD01190 AM02011-AS AM02014-SS AD02205 AM03262-AS AM03224-SS AD02698AM03107-AS AM03278-SS AD01191 AM02012-AS AM02014-SS AD02206 AM03262-ASAM03225-SS AD02699 AM03107-AS AM03289-SS AD01192 AM02013-AS AM02014-SSAD02207 AM03262-AS AM03226-SS AD02710 AM03486-AS AM03489-SS AD01193AM02015-AS AM02018-SS AD02208 AM03262-AS AM03227-SS AD02711 AM03487-ASAM03489-SS AD01194 AM02016-AS AM02018-SS AD02209 AM03262-AS AM03228-SSAD02712 AM03488-AS AM03489-SS AD01195 AM02017-AS AM02018-SS AD02210AM03262-AS AM03229-SS AD02713 AM02860-AS AM03489-SS AD01196 AM02019-ASAM02022-SS AD02211 AM03262-AS AM03230-SS AD02714 AM03490-AS AM03492-SSAD01197 AM02020-AS AM02022-SS AD02212 AM03262-AS AM03231-SS AD02715AM03491-AS AM03492-SS AD01198 AM02021-AS AM02022-SS AD02213 AM03262-ASAM03232-SS AD02716 AM02531-AS AM03492-SS AD01199 AM02023-AS AM02026-SSAD02214 AM03262-AS AM03233-SS AD02717 AM03107-AS AM03492-SS AD01200AM02024-AS AM02026-SS AD02215 AM03262-AS AM03234-SS AD02745 AM03107-ASAM03544-SS AD01201 AM02025-AS AM02026-SS AD02216 AM03262-AS AM03235-SSAD02746 AM03283-AS AM03544-SS AD01202 AM02027-AS AM02030-SS AD02217AM03262-AS AM03236-SS AD02747 AM03300-AS AM03544-SS AD01203 AM02028-ASAM02030-SS AD02218 AM03262-AS AM03237-SS AD02748 AM03107-AS AM03545-SSAD01204 AM02029-AS AM02030-SS AD02219 AM03263-AS AM03220-SS AD02749AM03283-AS AM03545-SS AD01205 AM02031-AS AM02034-SS AD02220 AM03263-ASAM03221-SS AD02750 AM03300-AS AM03545-SS AD01206 AM02032-AS AM02034-SSAD02221 AM03263-AS AM03222-SS AD02751 AM03107-AS AM03546-SS AD01207AM02033-AS AM02034-SS AD02222 AM03263-AS AM03223-SS AD02752 AM03283-ASAM03546-SS AD01208 AM02035-AS AM02038-SS AD02223 AM03263-AS AM03224-SSAD02753 AM03300-AS AM03546-SS AD01209 AM02036-AS AM02038-SS AD02224AM03263-AS AM03225-SS AD02754 AM02534-AS AM03547-SS AD01210 AM02037-ASAM02038-SS AD02225 AM03263-AS AM03226-SS AD02755 AM02857-AS AM03547-SSAD01211 AM02039-AS AM02042-SS AD02226 AM03263-AS AM03227-SS AD02819AM03377-AS AM03650-SS AD01212 AM02040-AS AM02042-SS AD02227 AM03263-ASAM03228-SS AD02820 AM03259-AS AM03650-SS AD01213 AM02041-AS AM02042-SSAD02228 AM03263-AS AM03229-SS AD02821 AM03129-AS AM03651-SS AD01328AM02240-AS AM02211-SS AD02229 AM03263-AS AM03230-SS AD02825 AM03655-ASAM03650-SS AD01329 AM02241-AS AM02212-SS AD02230 AM03263-AS AM03231-SSAD02826 AM03656-AS AM03650-SS AD01330 AM02242-AS AM02213-SS AD02231AM03263-AS AM03232-SS AD02827 AM03657-AS AM03650-SS AD01331 AM02243-ASAM02214-SS AD02232 AM03263-AS AM03233-SS AD02828 AM03658-AS AM03650-SSAD01332 AM02244-AS AM02215-SS AD02233 AM03263-AS AM03234-SS AD02829AM03659-AS AM03650-SS AD01333 AM02245-AS AM02216-SS AD02234 AM03263-ASAM03235-SS AD02830 AM03660-AS AM03650-SS AD01334 AM02246-AS AM02217-SSAD02235 AM03263-AS AM03236-SS AD02831 AM03661-AS AM03650-SS AD01335AM02247-AS AM02218-SS AD02236 AM03263-AS AM03237-SS AD02832 AM03269-ASAM03650-SS AD01336 AM02248-AS AM02219-SS AD02237 AM03264-AS AM03220-SSAD02841 AM03671-AS AM03670-SS AD01337 AM02249-AS AM02220-SS AD02238AM03264-AS AM03221-SS AD02842 AM03672-AS AM03546-SS AD01338 AM02250-ASAM02221-SS AD02239 AM03264-AS AM03222-SS AD02843 AM03673-AS AM03546-SSAD01339 AM02251-AS AM02222-SS AD02240 AM03264-AS AM03223-SS AD02844AM03674-AS AM03546-SS AD01340 AM02252-AS AM02223-SS AD02241 AM03264-ASAM03224-SS AD02845 AM03675-AS AM03546-SS AD01341 AM02253-AS AM02224-SSAD02242 AM03264-AS AM03225-SS AD02846 AM03676-AS AM03546-SS AD01342AM02254-AS AM02225-SS AD02243 AM03264-AS AM03226-SS AD02847 AM03677-ASAM03546-SS AD01343 AM02255-AS AM02226-SS AD02244 AM03264-AS AM03227-SSAD02848 AM03678-AS AM03650-SS AD01344 AM02256-AS AM02227-SS AD02245AM03264-AS AM03228-SS AD02849 AM03679-AS AM03650-SS AD01345 AM02257-ASAM02228-SS AD02246 AM03264-AS AM03229-SS AD02850 AM03680-AS AM03650-SSAD01346 AM02258-AS AM02229-SS AD02247 AM03264-AS AM03230-SS AD02851AM03681-AS AM03650-SS AD01347 AM02259-AS AM02230-SS AD02248 AM03264-ASAM03231-SS AD02852 AM03682-AS AM03650-SS AD01348 AM02260-AS AM02231-SSAD02249 AM03264-AS AM03232-SS AD02853 AM02860-AS AM03237-SS AD01349AM02261-AS AM02232-SS AD02250 AM03264-AS AM03233-SS AD02854 AM03377-ASAM03225-SS AD01350 AM02262-AS AM02233-SS AD02251 AM03264-AS AM03234-SSAD02855 AM03129-AS AM03683-SS AD01351 AM02263-AS AM02234-SS AD02252AM03264-AS AM03235-SS AD02907 AM02775-AS AM03741-SS AD01352 AM02264-ASAM02235-SS AD02253 AM03264-AS AM03236-SS AD02908 AM02775-AS AM03742-SSAD01353 AM02265-AS AM02236-SS AD02254 AM03264-AS AM03237-SS AD02909AM02775-AS AM03743-SS AD01354 AM02266-AS AM02237-SS AD02255 AM03265-ASAM03220-SS AD02910 AM03744-AS AM03457-SS AD01355 AM02267-AS AM02238-SSAD02256 AM03265-AS AM03221-SS AD02911 AM03745-AS AM03457-SS AD01356AM02268-AS AM02239-SS AD02257 AM03265-AS AM03222-SS AD02912 AM03745-ASAM03742-SS AD01462 AM02404-AS AM02441-SS AD02258 AM03265-AS AM03223-SSAD02913 AM02776-AS AM03746-SS AD01463 AM02406-AS AM02442-SS AD02259AM03265-AS AM03224-SS AD02914 AM02776-AS AM03747-SS AD01464 AM02408-ASAM02443-SS AD02260 AM03265-AS AM03225-SS AD02915 AM02776-AS AM03748-SSAD01465 AM02410-AS AM02444-SS AD02261 AM03265-AS AM03226-SS AD02916AM03749-AS AM03458-SS AD01466 AM02412-AS AM02445-SS AD02262 AM03265-ASAM03227-SS AD02917 AM03750-AS AM03458-SS AD01467 AM02414-AS AM02446-SSAD02263 AM03265-AS AM03228-SS AD02918 AM03750-AS AM03747-SS AD01468AM02416-AS AM02447-SS AD02264 AM03265-AS AM03229-SS AD02919 AM02788-ASAM03751-SS AD01469 AM02418-AS AM02448-SS AD02265 AM03265-AS AM03230-SSAD02920 AM02788-AS AM03752-SS AD01529 AM02531-AS AM02537-SS AD02266AM03265-AS AM03231-SS AD02921 AM02788-AS AM03753-SS AD01530 AM02532-ASAM02538-SS AD02267 AM03265-AS AM03232-SS AD02922 AM03754-AS AM03461-SSAD01531 AM02533-AS AM02539-SS AD02268 AM03265-AS AM03233-SS AD02923AM03755-AS AM03461-SS AD01532 AM02534-AS AM02540-SS AD02269 AM03265-ASAM03234-SS AD02924 AM03756-AS AM03461-SS AD01533 AM02535-AS AM02541-SSAD02270 AM03265-AS AM03235-SS AD02925 AM03756-AS AM03752-SS AD01534AM02536-AS AM02542-SS AD02271 AM03265-AS AM03236-SS AD02926 AM02791-ASAM03757-SS AD01708 AM02755-AS AM02793-SS AD02272 AM03265-AS AM03237-SSAD02927 AM02791-AS AM03758-SS AD01709 AM02756-AS AM02794-SS AD02273AM03266-AS AM03220-SS AD02928 AM02791-AS AM03759-SS AD01710 AM02757-ASAM02795-SS AD02274 AM03266-AS AM03221-SS AD02929 AM03760-AS AM03462-SSAD01711 AM02758-AS AM02796-SS AD02275 AM03266-AS AM03222-SS AD02930AM03761-AS AM03462-SS AD01712 AM02759-AS AM02797-SS AD02276 AM03266-ASAM03223-SS AD02931 AM03762-AS AM03462-SS AD01713 AM02760-AS AM02798-SSAD02277 AM03266-AS AM03224-SS AD02932 AM03762-AS AM03758-SS AD01714AM02761-AS AM02799-SS AD02278 AM03266-AS AM03225-SS AD03049 AM03856-ASAM03650-SS AD01715 AM02762-AS AM02800-SS AD02279 AM03266-AS AM03226-SSAD03050 AM03857-AS AM03651-SS AD01716 AM02763-AS AM02801-SS AD02280AM03266-AS AM03227-SS AD03051 AM03377-AS AM03859-SS AD01717 AM02764-ASAM02802-SS AD02281 AM03266-AS AM03228-SS AD03052 AM03129-AS AM03861-SSAD01718 AM02765-AS AM02803-SS AD02282 AM03266-AS AM03229-SS AD03053AM03862-AS AM03650-SS AD01719 AM02766-AS AM02804-SS AD02283 AM03266-ASAM03230-SS AD03054 AM03259-AS AM03859-SS AD01720 AM02767-AS AM02805-SSAD02284 AM03266-AS AM03231-SS AD03058 AM03866-AS AM03546-SS AD01721AM02768-AS AM02806-SS AD02285 AM03266-AS AM03232-SS AD03059 AM03867-ASAM03546-SS AD01722 AM02769-AS AM02807-SS AD02286 AM03266-AS AM03233-SSAD03060 AM03868-AS AM03546-SS AD01723 AM02770-AS AM02808-SS AD02287AM03266-AS AM03234-SS AD03061 AM03869-AS AM03546-SS AD01724 AM02771-ASAM02809-SS AD02288 AM03266-AS AM03235-SS AD03062 AM03870-AS AM03546-SSAD01725 AM02772-AS AM02810-SS AD02289 AM03266-AS AM03236-SS AD03063AM03871-AS AM03546-SS AD01726 AM02773-AS AM02811-SS AD02290 AM03266-ASAM03237-SS AD03064 AM03872-AS AM03546-SS AD01727 AM02774-AS AM02793-SSAD02291 AM03267-AS AM03220-SS AD03065 AM03873-AS AM03546-SS AD01728AM02775-AS AM02794-SS AD02292 AM03267-AS AM03221-SS AD03066 AM03874-ASAM03546-SS AD01729 AM02776-AS AM02795-SS AD02293 AM03267-AS AM03222-SSAD03067 AM03875-AS AM03546-SS AD01730 AM02777-AS AM02796-SS AD02294AM03267-AS AM03223-SS AD03068 AM03876-AS AM03546-SS AD01731 AM02778-ASAM02797-SS AD02295 AM03267-AS AM03224-SS AD03069 AM03877-AS AM03546-SSAD01732 AM02779-AS AM02798-SS AD02296 AM03267-AS AM03225-SS AD03070AM03878-AS AM03546-SS AD01733 AM02780-AS AM02799-SS AD02297 AM03267-ASAM03226-SS AD03071 AM03883-AS AM03879-SS AD01734 AM02781-AS AM02800-SSAD02298 AM03267-AS AM03227-SS AD03072 AM03884-AS AM03880-SS AD01735AM02782-AS AM02801-SS AD02299 AM03267-AS AM03228-SS AD03073 AM03883-ASAM03881-SS AD01736 AM02783-AS AM02802-SS AD02300 AM03267-AS AM03229-SSAD03074 AM03885-AS AM03882-SS AD01737 AM02784-AS AM02803-SS AD02301AM03267-AS AM03230-SS AD03075 AM03129-AS AM03546-SS AD01738 AM02785-ASAM02804-SS AD02302 AM03267-AS AM03231-SS AD03114 AM03929-AS AM03651-SSAD01739 AM02786-AS AM02805-SS AD02303 AM03267-AS AM03232-SS AD03115AM03930-AS AM03651-SS AD01740 AM02787-AS AM02806-SS AD02304 AM03267-ASAM03233-SS AD03116 AM03129-AS AM03928-SS AD01741 AM02788-AS AM02807-SSAD02305 AM03267-AS AM03234-SS AD03117 AM03929-AS AM03928-SS AD01742AM02789-AS AM02808-SS AD02306 AM03267-AS AM03235-SS AD03118 AM03930-ASAM03928-SS AD01743 AM02790-AS AM02809-SS AD02307 AM03267-AS AM03236-SSAD03119 AM03932-AS AM03650-SS AD01744 AM02791-AS AM02810-SS AD02308AM03267-AS AM03237-SS AD03120 AM03933-AS AM03650-SS AD01745 AM02792-ASAM02811-SS AD02309 AM03268-AS AM03220-SS AD03121 AM03377-AS AM03931-SSAD01746 AM02774-AS AM02812-SS AD02310 AM03268-AS AM03221-SS AD03122AM03932-AS AM03931-SS AD01747 AM02775-AS AM02813-SS AD02311 AM03268-ASAM03222-SS AD03123 AM03933-AS AM03931-SS AD01748 AM02776-AS AM02814-SSAD02312 AM03268-AS AM03223-SS AD03156 AM03969-AS AM03968-SS AD01749AM02777-AS AM02815-SS AD02313 AM03268-AS AM03224-SS AD03157 AM03971-ASAM03970-SS AD01750 AM02778-AS AM02816-SS AD02314 AM03268-AS AM03225-SSAD03158 AM03972-AS AM03970-SS AD01751 AM02779-AS AM02817-SS AD02315AM03268-AS AM03226-SS AD03159 AM03973-AS AM03970-SS AD01752 AM02780-ASAM02818-SS AD02316 AM03268-AS AM03227-SS AD03170 AM03823-AS AM03651-SSAD01753 AM02781-AS AM02819-SS AD02317 AM03268-AS AM03228-SS AD03171AM03824-AS AM03651-SS AD01754 AM02782-AS AM02820-SS AD02318 AM03268-ASAM03229-SS AD03172 AM03825-AS AM03651-SS AD01755 AM02783-AS AM02821-SSAD02319 AM03268-AS AM03230-SS AD03173 AM03826-AS AM03651-SS AD01756AM02784-AS AM02822-SS AD02320 AM03268-AS AM03231-SS AD03174 AM03827-ASAM03650-SS AD01757 AM02785-AS AM02823-SS AD02321 AM03268-AS AM03232-SSAD03175 AM03828-AS AM03650-SS AD01758 AM02786-AS AM02824-SS AD02322AM03268-AS AM03233-SS AD03272 AM02860-AS AM04138-SS AD01759 AM02787-ASAM02825-SS AD02323 AM03268-AS AM03234-SS AD03273 AM03377-AS AM04138-SSAD01760 AM02788-AS AM02826-SS AD02324 AM03268-AS AM03235-SS AD03274AM04132-AS AM04138-SS AD01761 AM02789-AS AM02827-SS AD02325 AM03268-ASAM03236-SS AD03275 AM04133-AS AM04138-SS AD01762 AM02790-AS AM02828-SSAD02326 AM03268-AS AM03237-SS AD03276 AM04134-AS AM04138-SS AD01763AM02791-AS AM02829-SS AD02327 AM03269-AS AM03220-SS AD03277 AM04135-ASAM04138-SS AD01764 AM02792-AS AM02830-SS AD02328 AM03269-AS AM03221-SSAD03278 AM04136-AS AM04138-SS AD01765 AM02857-AS AM02540-SS AD02329AM03269-AS AM03222-SS AD03279 AM04137-AS AM04138-SS AD01766 AM02858-ASAM02540-SS AD02330 AM03269-AS AM03223-SS AD03291 AM04150-AS AM04152-SSAD01767 AM02859-AS AM02540-SS AD02331 AM03269-AS AM03224-SS AD03327AM04150-AS AM04214-SS AD01768 AM02860-AS AM02540-SS AD02332 AM03269-ASAM03225-SS AD03341 AM04133-AS AM04233-SS AD01769 AM02859-AS AM02861-SSAD02333 AM03269-AS AM03226-SS AD03351 AM04250-AS AM03742-SS AD01770AM02860-AS AM02861-SS AD02334 AM03269-AS AM03227-SS AD03352 AM04251-ASAM03742-SS AD01772 AM02863-AS AM02541-SS AD02335 AM03269-AS AM03228-SSAD03353 AM04252-AS AM03742-SS AD01773 AM02864-AS AM02541-SS AD02336AM03269-AS AM03229-SS AD03354 AM04253-AS AM03747-SS AD01774 AM02865-ASAM02541-SS AD02337 AM03269-AS AM03230-SS AD03355 AM04254-AS AM03747-SSAD01780 AM02866-AS AM02541-SS AD02338 AM03269-AS AM03231-SS AD03356AM04255-AS AM03747-SS AD01803 AM02534-AS AM02941-SS AD02339 AM03269-ASAM03232-SS AD03357 AM04256-AS AM03752-SS AD01804 AM02534-AS AM02942-SSAD02340 AM03269-AS AM03233-SS AD03358 AM04257-AS AM03752-SS AD01805AM02943-AS AM02540-SS AD02341 AM03269-AS AM03234-SS AD03359 AM04258-ASAM03752-SS AD01806 AM02943-AS AM02941-SS AD02342 AM03269-AS AM03235-SSAD03360 AM04259-AS AM03758-SS AD01807 AM02943-AS AM02942-SS AD02343AM03269-AS AM03236-SS AD03361 AM04260-AS AM03758-SS AD01808 AM02944-ASAM02540-SS AD02344 AM03269-AS AM03237-SS AD03362 AM04261-AS AM03758-SSAD01809 AM02944-AS AM02941-SS AD02345 AM03270-AS AM03220-SS AD03421AM04133-AS AM04372-SS AD01810 AM02944-AS AM02942-SS AD02346 AM03270-ASAM03221-SS AD03424 AM04215-AS AM03546-SS AD01811 AM02945-AS AM02540-SSAD02347 AM03270-AS AM03222-SS AD03425 AM04216-AS AM03546-SS AD01812AM02945-AS AM02941-SS AD02348 AM03270-AS AM03223-SS AD03426 AM04217-ASAM03546-SS AD01813 AM02945-AS AM02942-SS AD02349 AM03270-AS AM03224-SSAD03427 AM04218-AS AM03546-SS AD01814 AM02535-AS AM02946-SS AD02350AM03270-AS AM03225-SS AD03428 AM04219-AS AM03546-SS AD01815 AM02535-ASAM02947-SS AD02351 AM03270-AS AM03226-SS AD03430 AM04377-AS AM04381-SSAD01816 AM02535-AS AM02948-SS AD02352 AM03270-AS AM03227-SS AD03431AM04378-AS AM04382-SS AD01817 AM02535-AS AM02949-SS AD02353 AM03270-ASAM03228-SS AD03432 AM04379-AS AM04381-SS AD01818 AM02950-AS AM02541-SSAD02354 AM03270-AS AM03229-SS AD03433 AM04380-AS AM04382-SS AD01819AM02950-AS AM02946-SS AD02355 AM03270-AS AM03230-SS AD03434 AM04383-ASAM04391-SS AD01820 AM02950-AS AM02947-SS AD02356 AM03270-AS AM03231-SSAD03435 AM04384-AS AM04392-SS AD01821 AM02950-AS AM02948-SS AD02357AM03270-AS AM03232-SS AD03436 AM04385-AS AM04391-SS AD01822 AM02950-ASAM02949-SS AD02358 AM03270-AS AM03233-SS AD03437 AM04386-AS AM04392-SSAD01823 AM02951-AS AM02541-SS AD02359 AM03270-AS AM03234-SS AD03438AM04387-AS AM04391-SS AD01824 AM02951-AS AM02946-SS AD02360 AM03270-ASAM03235-SS AD03439 AM04388-AS AM04392-SS AD01825 AM02951-AS AM02947-SSAD02361 AM03270-AS AM03236-SS AD03440 AM04389-AS AM04391-SS AD01826AM02951-AS AM02948-SS AD02362 AM03270-AS AM03237-SS AD03441 AM04390-ASAM04392-SS AD01827 AM02951-AS AM02949-SS AD02363 AM03271-AS AM03220-SSAD03460 AM03300-AS AM04412-SS AD01828 AM02952-AS AM02541-SS AD02364AM03271-AS AM03221-SS AD03461 AM04413-AS AM04414-SS AD01829 AM02952-ASAM02946-SS AD02365 AM03271-AS AM03222-SS AD03462 AM04415-AS AM04416-SSAD01830 AM02952-AS AM02947-SS AD02366 AM03271-AS AM03223-SS AD03463AM04417-AS AM04412-SS AD01831 AM02952-AS AM02948-SS AD02367 AM03271-ASAM03224-SS AD03494 AM04437-AS AM03742-SS AD01832 AM02952-AS AM02949-SSAD02368 AM03271-AS AM03225-SS AD03495 AM04438-AS AM03747-SS AD01895AM02863-AS AM03030-SS AD02369 AM03271-AS AM03226-SS AD03496 AM04439-ASAM03752-SS AD01896 AM02865-AS AM03036-SS AD02370 AM03271-AS AM03227-SSAD03497 AM04440-AS AM03758-SS AD01897 AM02865-AS AM03037-SS AD02371AM03271-AS AM03228-SS AD03536 AM03972-AS AM04496-SS AD01898 AM02865-ASAM03038-SS AD02372 AM03271-AS AM03229-SS AD03537 AM02860-AS AM04497-SSAD01899 AM03040-AS AM03039-SS AD02373 AM03271-AS AM03230-SS AD03538AM03972-AS AM04499-SS AD01900 AM03041-AS AM03039-SS AD02374 AM03271-ASAM03231-SS AD03539 AM04415-AS AM04498-SS AD01901 AM03041-AS AM03042-SSAD02375 AM03271-AS AM03232-SS AD03540 AM03972-AS AM04500-SS AD01902AM02863-AS AM03042-SS AD02376 AM03271-AS AM03233-SS AD03541 AM04501-ASAM03970-SS AD01903 AM03043-AS AM03042-SS AD02377 AM03271-AS AM03234-SSAD03542 AM02860-AS AM04502-SS AD01912 AM03065-AS AM03060-SS AD02378AM03271-AS AM03235-SS AD03547 AM04507-AS AM04498-SS AD01913 AM03066-ASAM03060-SS AD02379 AM03271-AS AM03236-SS AD03548 AM02860-AS AM04498-SSAD01914 AM03067-AS AM03060-SS AD02380 AM03271-AS AM03237-SS AD03549AM04507-AS AM04502-SS AD01915 AM03068-AS AM03060-SS AD02381 AM03272-ASAM03220-SS AD03573 AM04539-AS AM04535-SS AD01916 AM03069-AS AM03060-SSAD02382 AM03272-AS AM03221-SS AD03574 AM04540-AS AM04536-SS AD01917AM03070-AS AM03060-SS AD02383 AM03272-AS AM03222-SS AD03575 AM04541-ASAM04537-SS AD01918 AM03065-AS AM03061-SS AD02384 AM03272-AS AM03223-SSAD03576 AM04542-AS AM04538-SS AD01919 AM03066-AS AM03061-SS AD02385AM03272-AS AM03224-SS AD03577 AM04544-AS AM04543-SS AD01920 AM03067-ASAM03061-SS AD02386 AM03272-AS AM03225-SS AD03578 AM04545-AS AM04500-SSAD01921 AM03068-AS AM03061-SS AD02387 AM03272-AS AM03226-SS AD03579AM04546-AS AM04500-SS AD01922 AM03069-AS AM03061-SS AD02388 AM03272-ASAM03227-SS AD03603 AM04582-AS AM04578-SS AD01923 AM03070-AS AM03061-SSAD02389 AM03272-AS AM03228-SS AD03604 AM04583-AS AM04578-SS AD01924AM03065-AS AM03062-SS AD02390 AM03272-AS AM03229-SS AD03605 AM04584-ASAM04578-SS AD01925 AM03066-AS AM03062-SS AD02391 AM03272-AS AM03230-SSAD03606 AM04585-AS AM04578-SS AD01926 AM03067-AS AM03062-SS AD02392AM03272-AS AM03231-SS AD03607 AM04586-AS AM04578-SS AD01927 AM03068-ASAM03062-SS AD02393 AM03272-AS AM03232-SS AD03608 AM04587-AS AM04578-SSAD01928 AM03069-AS AM03062-SS AD02394 AM03272-AS AM03233-SS AD03609AM04584-AS AM04588-SS AD01929 AM03070-AS AM03062-SS AD02395 AM03272-ASAM03234-SS AD03610 AM04584-AS AM04579-SS AD01930 AM03065-AS AM03037-SSAD02396 AM03272-AS AM03235-SS AD03611 AM04584-AS AM04580-SS AD01931AM03066-AS AM03037-SS AD02397 AM03272-AS AM03236-SS AD03612 AM04584-ASAM04581-SS AD01932 AM03067-AS AM03037-SS AD02398 AM03272-AS AM03237-SSAD03627 AM04609-AS AM03970-SS AD01933 AM03068-AS AM03037-SS AD02399AM03273-AS AM03220-SS AD03628 AM04610-AS AM03970-SS AD01934 AM03069-ASAM03037-SS AD02400 AM03273-AS AM03221-SS AD03629 AM03972-AS AM04611-SSAD01935 AM03070-AS AM03037-SS AD02401 AM03273-AS AM03222-SS AD03630AM03972-AS AM04612-SS AD01936 AM03065-AS AM03064-SS AD02402 AM03273-ASAM03223-SS AD03668 AM04501-AS AM04500-SS AD01937 AM03066-AS AM03064-SSAD02403 AM03273-AS AM03224-SS AD03671 AM04677-AS AM04669-SS AD01938AM03067-AS AM03064-SS AD02404 AM03273-AS AM03225-SS AD03672 AM04678-ASAM04670-SS AD01939 AM03068-AS AM03064-SS AD02405 AM03273-AS AM03226-SSAD03673 AM04679-AS AM04671-SS AD01940 AM03069-AS AM03064-SS AD02406AM03273-AS AM03227-SS AD03674 AM04680-AS AM04672-SS AD01941 AM03070-ASAM03064-SS AD02407 AM03273-AS AM03228-SS AD03675 AM04681-AS AM04673-SSAD01976 AM03119-AS AM02540-SS AD02408 AM03273-AS AM03229-SS AD03676AM02860-AS AM04674-SS AD01977 AM03120-AS AM02540-SS AD02409 AM03273-ASAM03230-SS AD03677 AM02860-AS AM04675-SS AD01978 AM03121-AS AM02540-SSAD02410 AM03273-AS AM03231-SS AD03678 AM02860-AS AM04676-SS AD01979AM02857-AS AM03122-SS AD02411 AM03273-AS AM03232-SS AD03705 AM04501-ASAM04726-SS AD01980 AM02857-AS AM03123-SS AD02412 AM03273-AS AM03233-SSAD03706 AM04501-AS AM04727-SS AD01981 AM03119-AS AM03122-SS AD02413AM03273-AS AM03234-SS AD03707 AM04501-AS AM04728-SS AD01982 AM02857-ASAM03124-SS AD02414 AM03273-AS AM03235-SS AD03708 AM04544-AS AM04729-SSAD01983 AM03107-AS AM02537-SS AD02415 AM03273-AS AM03236-SS AD03713AM04733-AS AM04138-SS AD01984 AM03108-AS AM02537-SS AD02416 AM03273-ASAM03237-SS AD03714 AM04734-AS AM04138-SS AD01985 AM03107-AS AM03125-SSAD02417 AM03274-AS AM03220-SS AD03715 AM04735-AS AM04138-SS AD01986AM03107-AS AM03126-SS AD02418 AM03274-AS AM03221-SS AD03716 AM04736-ASAM04138-SS AD01987 AM03127-AS AM02537-SS AD02419 AM03274-AS AM03222-SSAD03717 AM02860-AS AM04737-SS AD01988 AM03129-AS AM03128-SS AD02420AM03274-AS AM03223-SS AD03720 AM03884-AS AM04741-SS AD01989 AM03130-ASAM02540-SS AD02421 AM03274-AS AM03224-SS AD03721 AM03972-AS AM04742-SSAD01990 AM03131-AS AM02540-SS AD02422 AM03274-AS AM03225-SS AD03722AM03972-AS AM04743-SS AD02001 AM02860-AS AM02942-SS AD02423 AM03274-ASAM03226-SS AD03723 AM03972-AS AM04744-SS AD02002 AM02857-AS AM03144-SSAD02424 AM03274-AS AM03227-SS AD03760 AM04805-AS AM04803-SS AD02003AM03149-AS AM02540-SS AD02425 AM03274-AS AM03228-SS AD03761 AM04501-ASAM04804-SS AD02004 AM03149-AS AM02941-SS AD02426 AM03274-AS AM03229-SSAD03762 AM04805-AS AM04807-SS AD02005 AM03149-AS AM02942-SS AD02427AM03274-AS AM03230-SS AD03763 AM03884-AS AM04729-SS AD02006 AM03150-ASAM02540-SS AD02428 AM03274-AS AM03231-SS AD03764 AM03884-AS AM04806-SSAD02007 AM03150-AS AM02941-SS AD02429 AM03274-AS AM03232-SS AD03765AM04501-AS AM04611-SS AD02008 AM03150-AS AM02942-SS AD02430 AM03274-ASAM03233-SS AD03766 AM04501-AS AM04808-SS AD02009 AM03151-AS AM02540-SSAD02431 AM03274-AS AM03234-SS AD03767 AM04501-AS AM04809-SS AD02010AM03151-AS AM02941-SS AD02432 AM03274-AS AM03235-SS AD03768 AM04501-ASAM04810-SS AD02011 AM03151-AS AM02942-SS AD02433 AM03274-AS AM03236-SSAD03769 AM04501-AS AM04811-SS AD02075 AM03255-AS AM03220-SS AD02434AM03274-AS AM03237-SS AD03770 AM04501-AS AM04812-SS AD02076 AM03255-ASAM03221-SS AD02435 AM03255-AS AM03238-SS AD03771 AM02860-AS AM04813-SSAD02077 AM03255-AS AM03222-SS AD02436 AM03256-AS AM03238-SS AD03801AM04821-AS AM04816-SS AD02078 AM03255-AS AM03223-SS AD02437 AM03255-ASAM03240-SS AD03802 AM04822-AS AM04817-SS AD02079 AM03255-AS AM03224-SSAD02438 AM03256-AS AM03240-SS AD03803 AM04823-AS AM04816-SS AD02080AM03255-AS AM03225-SS AD02439 AM03255-AS AM02942-SS AD03804 AM04821-ASAM04835-SS AD02081 AM03255-AS AM03226-SS AD02440 AM03256-AS AM02942-SSAD03805 AM04824-AS AM04819-SS AD02082 AM03255-AS AM03227-SS AD02462AM02857-AS AM03330-SS AD03806 AM04824-AS AM04820-SS AD02083 AM03255-ASAM03228-SS AD02463 AM03331-AS AM01223-SS AD03841 AM04871-AS AM04862-SSAD02084 AM03255-AS AM03229-SS AD02464 AM03107-AS AM03291-SS AD03842AM02860-AS AM04863-SS AD02085 AM03255-AS AM03230-SS AD02465 AM03279-ASAM03291-SS AD03843 AM04872-AS AM04138-SS AD02086 AM03255-AS AM03231-SSAD02466 AM03280-AS AM03291-SS AD03844 AM04539-AS AM04864-SS AD02087AM03255-AS AM03232-SS AD02467 AM03281-AS AM03291-SS AD03845 AM03300-ASAM04865-SS AD02088 AM03255-AS AM03233-SS AD02468 AM03282-AS AM03291-SSAD03846 AM04873-AS AM04412-SS AD02089 AM03255-AS AM03234-SS AD02469AM03283-AS AM03291-SS AD03847 AM04874-AS AM04866-SS AD02090 AM03255-ASAM03235-SS AD02470 AM03284-AS AM03291-SS AD03848 AM04874-AS AM04867-SSAD02091 AM03255-AS AM03236-SS AD02471 AM03300-AS AM03291-SS AD03849AM04875-AS AM04867-SS AD02092 AM03255-AS AM03237-SS AD02472 AM03301-ASAM03291-SS AD03850 AM04876-AS AM04866-SS AD02093 AM03256-AS AM03220-SSAD02473 AM03107-AS AM03292-SS AD03851 AM04877-AS AM04866-SS AD02094AM03256-AS AM03221-SS AD02474 AM03279-AS AM03292-SS AD03852 AM04877-ASAM04867-SS AD02095 AM03256-AS AM03222-SS AD02475 AM03280-AS AM03292-SSAD03853 AM04874-AS AM04868-SS AD02096 AM03256-AS AM03223-SS AD02476AM03281-AS AM03292-SS AD03854 AM04874-AS AM04869-SS AD02097 AM03256-ASAM03224-SS AD02477 AM03282-AS AM03292-SS AD03855 AM04875-AS AM04869-SSAD02098 AM03256-AS AM03225-SS AD02478 AM03283-AS AM03292-SS AD03856AM04874-AS AM04870-SS AD02099 AM03256-AS AM03226-SS AD02479 AM03284-ASAM03292-SS AD03857 AM03972-AS AM04808-SS AD02100 AM03256-AS AM03227-SSAD02480 AM03300-AS AM03292-SS AD03858 AM03972-AS AM04811-SS AD02101AM03256-AS AM03228-SS AD02481 AM03301-AS AM03292-SS AD03859 AM04822-ASAM04819-SS AD02102 AM03256-AS AM03229-SS AD02482 AM03107-AS AM03293-SSAD03860 AM04878-AS AM04819-SS AD02103 AM03256-AS AM03230-SS AD02483AM03279-AS AM03293-SS AD03861 AM04878-AS AM04820-SS AD02104 AM03256-ASAM03231-SS AD02484 AM03280-AS AM03293-SS AD03862 AM04879-AS AM04138-SSAD02105 AM03256-AS AM03232-SS AD02485 AM03281-AS AM03293-SS AD03863AM04879-AS AM04863-SS AD02106 AM03256-AS AM03233-SS AD02486 AM03282-ASAM03293-SS AD03864 AM04880-AS AM04138-SS AD02107 AM03256-AS AM03234-SSAD02487 AM03283-AS AM03293-SS AD03920 AM04969-AS AM04138-SS AD02108AM03256-AS AM03235-SS AD02488 AM03284-AS AM03293-SS AD03921 AM04970-ASAM04412-SS AD02109 AM03256-AS AM03236-SS AD02489 AM03300-AS AM03293-SSAD03922 AM04971-AS AM04867-SS AD02110 AM03256-AS AM03237-SS AD02490AM03301-AS AM03293-SS AD03923 AM04971-AS AM04869-SS AD02111 AM03257-ASAM03220-SS AD02491 AM03107-AS AM03294-SS AD03924 AM04972-AS AM04820-SSAD02112 AM03257-AS AM03221-SS AD02492 AM03279-AS AM03294-SS AD03925AM04972-AS AM04819-SS AD02113 AM03257-AS AM03222-SS AD02493 AM03280-ASAM03294-SS AD03931 AM04979-AS AM04978-SS AD02114 AM03257-AS AM03223-SSAD02494 AM03281-AS AM03294-SS AD03932 AM04979-AS AM04811-SS AD02115AM03257-AS AM03224-SS AD02495 AM03282-AS AM03294-SS AD03933 AM04979-ASAM04869-SS AD02116 AM03257-AS AM03225-SS AD02496 AM03283-AS AM03294-SSAD04017 AM03300-AS AM05070-SS AD02117 AM03257-AS AM03226-SS AD02497AM03284-AS AM03294-SS AD04018 AM03972-AS AM05072-SS AD02118 AM03257-ASAM03227-SS AD02498 AM03300-AS AM03294-SS AD04017 AM03300-AS AM05070-SSAD02119 AM03257-AS AM03228-SS AD02499 AM03301-AS AM03294-SS AD04018AM03972-AS AM05072-SS AD04170 AM03972-AS AM05341-SS AD04171 AM04877-ASAM05342-SS AD04110 AM04875-AS AM04866-SS AD04263 AM04879-AS AM05489-SSAD04272 AM04979-AS AM05499-SS AD04281 AM05496-AS AM04412-SS AD04264AM05490-AS AM04416-SS AD04273 AM03972-AS AM05494-SS AD04282 AM04874-ASAM05503-SS AD04265 AM05490-AS AM05491-SS AD04274 AM05498-AS AM05494-SSAD04283 AM04874-AS AM05502-SS AD04266 AM05492-AS AM04496-SS AD04275AM04979-AS AM05494-SS AD04284 AM04874-AS AM05506-SS AD04267 AM05493-ASAM04496-SS AD04276 AM03972-AS AM05501-SS AD04285 AM04877-AS AM05503-SSAD04268 AM05498-AS AM04496-SS AD04277 AM05498-AS AM05501-SS AD04286AM05497-AS AM05502-SS AD04269 AM04979-AS AM04496-SS AD04278 AM04979-ASAM05501-SS AD04287 AM05497-AS AM05506-SS AD04270 AM03972-AS AM05499-SSAD04279 AM03300-AS AM05500-SS AD04288 AM04874-AS AM05504-SS AD04271AM05498-AS AM05499-SS AD04280 AM05495-AS AM04412-SS AD04289 AM04874-ASAM05505-SS

TABLE 3B LPA RNAi agent duplexes with Duplex ID numbers. Antisense SenseDuplex ID Strand ID Strand ID SD0001 1533-AS00 1533-SS00 SD00021533-AS01 1533-SS00 SD0003 1533-AS02 1533-SS00 SD0004 1533-AS031533-SS00 SD0005 1533-AS04 1533-SS00 SD0006 1533-AS05 1533-SS00 SD00071533-AS06 1533-SS00 SD0008 1533-AS07 1533-SS00 SD0009 1533-AS081533-SS00 SD0010 1533-AS09 1533-SS00 SD0011 1533-AS10 1533-SS00 SD00121533-AS11 1533-SS00 SD0013 1533-AS12 1533-SS00 SD0014 1533-AS131533-SS00 SD0015 1533-AS14 1533-SS00 SD0016 1533-AS00 1533-SS01 SD00171533-AS01 1533-SS01 SD0018 1533-AS02 1533-SS01 SD0019 1533-AS031533-SS01 SD0020 1533-AS04 1533-SS01 SD0021 1533-AS05 1533-SS01 SD00221533-AS06 1533-SS01 SD0023 1533-AS07 1533-SS01 SD0024 1533-AS081533-SS01 SD0025 1533-AS09 1533-SS01 SD0026 1533-AS10 1533-SS01 SD00271533-AS11 1533-SS01 SD0028 1533-AS12 1533-SS01 SD0029 1533-AS131533-SS01 SD0030 1533-AS14 1533-SS01 SD0031 1533-AS00 1533-SS02 SD00321533-AS01 1533-SS02 SD0033 1533-AS02 1533-SS02 SD0034 1533-AS031533-SS02 SD0035 1533-AS04 1533-SS02 SD0036 1533-AS05 1533-SS02 SD00371533-AS06 1533-SS02 SD0038 1533-AS07 1533-SS02 SD0039 1533-AS081533-SS02 SD0040 1533-AS09 1533-SS02 SD0041 1533-AS10 1533-SS02 SD00421533-AS11 1533-SS02 SD0043 1533-AS12 1533-SS02 SD0044 1533-AS131533-SS02 SD0045 1533-AS14 1533-SS02 SD0046 1533-AS00 1533-SS03 SD00471533-AS01 1533-SS03 SD0048 1533-AS02 1533-SS03 SD0049 1533-AS031533-SS03 SD0050 1533-AS04 1533-SS03 SD0051 1533-AS05 1533-SS03 SD00521533-AS06 1533-SS03 SD0053 1533-AS07 1533-SS03 SD0054 1533-AS081533-SS03 SD0055 1533-AS09 1533-SS03 SD0056 1533-AS10 1533-SS03 SD00571533-AS11 1533-SS03 SD0058 1533-AS12 1533-SS03 SD0059 1533-AS131533-SS03 SD0060 1533-AS14 1533-SS03 SD0061 1533-AS00 1533-SS04 SD00621533-AS01 1533-SS04 SD0063 1533-AS02 1533-SS04 SD0064 1533-AS031533-SS04 SD0065 1533-AS04 1533-SS04 SD0066 1533-AS05 1533-SS04 SD00671533-AS06 1533-SS04 SD0068 1533-AS07 1533-SS04 SD0069 1533-AS081533-SS04 SD0070 1533-AS09 1533-SS04 SD0071 1533-AS10 1533-SS04 SD00721533-AS11 1533-SS04 SD0073 1533-AS12 1533-SS04 SD0074 1533-AS131533-SS04 SD0075 1533-AS14 1533-SS04 SD0076 1533-AS00 1533-SS05 SD00771533-AS01 1533-SS05 SD0078 1533-AS02 1533-SS05 SD0079 1533-AS031533-SS05 SD0080 1533-AS04 1533-SS05 SD0081 1533-AS05 1533-SS05 SD00821533-AS06 1533-SS05 SD0083 1533-AS07 1533-SS05 SD0084 1533-AS081533-SS05 SD0085 1533-AS09 1533-SS05 SD0086 1533-AS10 1533-SS05 SD00871533-AS11 1533-SS05 SD0088 1533-AS12 1533-SS05 SD0089 1533-AS131533-SS05 SD0090 1533-AS14 1533-SS05 SD0091 1533-AS00 1533-SS06 SD00921533-AS01 1533-SS06 SD0093 1533-AS02 1533-SS06 SD0094 1533-AS031533-SS06 SD0095 1533-AS04 1533-SS06 SD0096 1533-AS05 1533-SS06 SD00971533-AS06 1533-SS06 SD0098 1533-AS07 1533-SS06 SD0099 1533-AS081533-SS06 SD0100 1533-AS09 1533-SS06 SD0101 1533-AS10 1533-SS06 SD01021533-AS11 1533-SS06 SD0103 1533-AS12 1533-SS06 SD0104 1533-AS131533-SS06 SD0105 1533-AS14 1533-SS06 SD0106 1533-AS00 1533-SS07 SD01071533-AS01 1533-SS07 SD0108 1533-AS02 1533-SS07 SD0109 1533-AS031533-SS07 SD0110 1533-AS04 1533-SS07 SD0111 1533-AS05 1533-SS07 SD01121533-AS06 1533-SS07 SD0113 1533-AS07 1533-SS07 SD0114 1533-AS081533-SS07 SD0115 1533-AS09 1533-SS07 SD0116 1533-AS10 1533-SS07 SD01171533-AS11 1533-SS07 SD0118 1533-AS12 1533-SS07 SD0119 1533-AS131533-SS07 SD0120 1533-AS14 1533-SS07 SD0121 1533-AS00 1533-SS08 SD01221533-AS01 1533-SS08 SD0123 1533-AS02 1533-SS08 SD0124 1533-AS031533-SS08 SD0125 1533-AS04 1533-SS08 SD0126 1533-AS05 1533-SS08 SD01271533-AS06 1533-SS08 SD0128 1533-AS07 1533-SS08 SD0129 1533-AS081533-SS08 SD0130 1533-AS09 1533-SS08 SD0131 1533-AS10 1533-SS08 SD01321533-AS11 1533-SS08 SD0133 1533-AS12 1533-SS08 SD0134 1533-AS131533-SS08 SD0135 1533-AS14 1533-SS08 SD0136 1533-AS00 1533-SS09 SD01371533-AS01 1533-SS09 SD0138 1533-AS02 1533-SS09 SD0139 1533-AS031533-SS09 SD0140 1533-AS04 1533-SS09 SD0141 1533-AS05 1533-SS09 SD01421533-AS06 1533-SS09 SD0143 1533-AS07 1533-SS09 SD0144 1533-AS081533-SS09 SD0145 1533-AS09 1533-SS09 SD0146 1533-AS10 1533-SS09 SD01471533-AS11 1533-SS09 SD0148 1533-AS12 1533-SS09 SD0149 1533-AS131533-SS09 SD0150 1533-AS14 1533-SS09 SD0151 1533-AS00 1533-SS01 SD01521533-AS01 1533-SS01 SD0153 1533-AS02 1533-SS01 SD0154 1533-AS031533-SS01 SD0155 1533-AS04 1533-SS01 SD0156 1533-AS05 1533-SS01 SD01571533-AS06 1533-SS01 SD0158 1533-AS07 1533-SS01 SD0159 1533-AS081533-SS01 SD0160 1533-AS09 1533-SS01 SD0161 1533-AS10 1533-SS01 SD01621533-AS11 1533-SS01 SD0163 1533-AS12 1533-SS01 SD0164 1533-AS131533-SS01 SD0165 1533-AS14 1533-SS01 SD0166 1533-AS00 1533-SS01 SD01671533-AS01 1533-SS01 SD0168 1533-AS02 1533-SS01 SD0169 1533-AS031533-SS01 SD0170 1533-AS04 1533-SS01 SD0171 1533-AS05 1533-SS01 SD01721533-AS06 1533-SS01 SD0173 1533-AS07 1533-SS01 SD0174 1533-AS081533-SS01 SD0175 1533-AS09 1533-SS01 SD0176 1533-AS10 1533-SS01 SD01771533-AS11 1533-SS01 SD0178 1533-AS12 1533-SS01 SD0179 1533-AS131533-SS01 SD0180 1533-AS14 1533-SS01 SD0181 1533-AS00 1533-SS02 SD01821533-AS01 1533-SS02 SD0183 1533-AS02 1533-SS02 SD0184 1533-AS031533-SS02 SD0185 1533-AS04 1533-SS02 SD0186 1533-AS05 1533-SS02 SD01871533-AS06 1533-SS02 SD0188 1533-AS07 1533-SS02 SD0189 1533-AS081533-SS02 SD0190 1533-AS09 1533-SS02 SD0191 1533-AS10 1533-SS02 SD01921533-AS11 1533-SS02 SD0193 1533-AS12 1533-SS02 SD0194 1533-AS131533-SS02 SD0195 1533-AS14 1533-SS02 SD0196 1533-AS00 1533-CfinSS SD01971533-AS01 1533-CfinSS SD0198 1533-AS02 1533-CfinSS SD0199 1533-AS031533-CfinSS SD0200 1533-AS04 1533-CfinSS SD0201 1533-AS05 1533-CfinSSSD0202 1533-AS06 1533-CfinSS SD0203 1533-AS07 1533-CfinSS SD02041533-AS08 1533-CfinSS SD0205 1533-AS09 1533-CfinSS SD0206 1533-AS101533-CfinSS SD0207 1533-AS11 1533-CfinSS SD0208 1533-AS12 1533-CfinSSSD0209 1533-AS13 1533-CfinSS SD0210 1533-AS14 1533-CfinSS SD02111533-CfinAS 1533-SS00 SD0212 1533-CfinAS 1533-SS01 SD0213 1533-CfinAS1533-SS02 SD0214 1533-CfinAS 1533-SS03 SD0215 1533-CfinAS 1533-SS04SD0216 1533-CfinAS 1533-SS05 SD0217 1533-CfinAS 1533-SS06 SD02181533-CfinAS 1533-SS07 SD0219 1533-CfinAS 1533-SS08 SD0220 1533-CfinAS1533-SS09 SD0221 1533-CfinAS 1533-SS10 SD0222 1533-CfinAS 1533-SS11SD0223 1533-CfinAS 1533-SS12 SD0224 1533-CfinAS 1533-SS13 SD02251533-CfinAS 1533-SS14 SD0226 1533-CfinAS 1533-SS15 SD0227 1533-CfinAS1533-SS16 SD0228 1533-CfinAS 1533-SS17 SD0229 1533-CfinAS 1533-SS18SD0230 1533-CfinAS 1533-SS19 SD0231 1533-CfinAS 1533-SS20 SD02321533-AS00 1533-SS12 SD0233 1533-AS01 1533-SS12 SD0234 1533-AS021533-SS12 SD0235 1533-AS03 1533-SS12 SD0236 1533-AS04 1533-SS12 SD02371533-AS05 1533-SS12 SD0238 1533-AS06 1533-SS12 SD0239 1533-AS071533-SS12 SD0240 1533-AS08 1533-SS12 SD0241 1533-AS09 1533-SS12 SD02421533-AS10 1533-SS12 SD0243 1533-AS11 1533-SS12 SD0244 1533-AS121533-SS12 SD0245 1533-AS13 1533-SS12 SD0246 1533-AS14 1533-SS12 SD02471533-AS00 1533-SS13 SD0248 1533-AS01 1533-SS13 SD0249 1533-AS021533-SS13 SD0250 1533-AS03 1533-SS13 SD0251 1533-AS04 1533-SS13 SD02521533-AS05 1533-SS13 SD0253 1533-AS06 1533-SS13 SD0254 1533-AS071533-SS13 SD0255 1533-AS08 1533-SS13 SD0256 1533-AS09 1533-SS13 SD02571533-AS10 1533-SS13 SD0258 1533-AS11 1533-SS13 SD0259 1533-AS121533-SS13 SD0260 1533-AS13 1533-SS13 SD0261 1533-AS14 1533-SS13 SD02621533-AS00 1533-SS14 SD0263 1533-AS01 1533-SS14 SD0264 1533-AS021533-SS14 SD0265 1533-AS03 1533-SS14 SD0266 1533-AS04 1533-SS14 SD02671533-AS05 1533-SS14 SD0268 1533-AS06 1533-SS14 SD0269 1533-AS071533-SS14 SD0270 1533-AS08 1533-SS14 SD0271 1533-AS09 1533-SS14 SD02721533-AS10 1533-SS14 SD0273 1533-AS11 1533-SS14 SD0274 1533-AS121533-SS14 SD0275 1533-AS13 1533-SS14 SD0276 1533-AS14 1533-SS14 SD02771533-AS00 1533-SS15 SD0278 1533-AS01 1533-SS15 SD0279 1533-AS021533-SS15 SD0280 1533-AS03 1533-SS15 SD0281 1533-AS04 1533-SS15 SD02821533-AS05 1533-SS15 SD0283 1533-AS06 1533-SS15 SD0284 1533-AS071533-SS15 SD0285 1533-AS08 1533-SS15 SD0286 1533-AS09 1533-SS15 SD02871533-AS10 1533-SS15 SD0288 1533-AS11 1533-SS15 SD0289 1533-AS121533-SS15 SD0290 1533-AS13 1533-SS15 SD0291 1533-AS14 1533-SS15 SD02921533-AS00 1533-SS16 SD0293 1533-AS01 1533-SS16 SD0294 1533-AS021533-SS16 SD0295 1533-AS03 1533-SS16 SD0296 1533-AS04 1533-SS16 SD02971533-AS05 1533-SS16 SD0298 1533-AS06 1533-SS16 SD0299 1533-AS071533-SS16 SD0300 1533-AS08 1533-SS16 SD0301 1533-AS09 1533-SS16 SD03021533-AS10 1533-SS16 SD0303 1533-AS11 1533-SS16 SD0304 1533-AS121533-SS16 SD0305 1533-AS13 1533-SS16 SD0306 1533-AS14 1533-SS16 SD03071533-AS00 1533-SS17 SD0308 1533-AS01 1533-SS17 SD0309 1533-AS021533-SS17 SD0310 1533-AS03 1533-SS17 SD0311 1533-AS04 1533-SS17 SD03121533-AS05 1533-SS17 SD0313 1533-AS06 1533-SS17 SD0314 1533-AS071533-SS17 SD0315 1533-AS08 1533-SS17 SD0316 1533-AS09 1533-SS17 SD03171533-AS10 1533-SS17 SD0318 1533-AS11 1533-SS17 SD0319 1533-AS121533-SS17 SD0320 1533-AS13 1533-SS17 SD0321 1533-AS14 1533-SS17 SD03221533-AS00 1533-SS18 SD0323 1533-AS01 1533-SS18 SD0324 1533-AS021533-SS18 SD0325 1533-AS03 1533-SS18 SD0326 1533-AS04 1533-SS18 SD03271533-AS05 1533-SS18 SD0328 1533-AS06 1533-SS18 SD0329 1533-AS071533-SS18 SD0330 1533-AS08 1533-SS18 SD0331 1533-AS09 1533-SS18 SD03321533-AS10 1533-SS18 SD0333 1533-AS11 1533-SS18 SD0334 1533-AS121533-SS18 SD0335 1533-AS13 1533-SS18 SD0336 1533-AS14 1533-SS18 SD03371533-AS00 1533-SS19 SD0338 1533-AS01 1533-SS19 SD0339 1533-AS021533-SS19 SD0340 1533-AS03 1533-SS19 SD0341 1533-AS04 1533-SS19 SD03421533-AS05 1533-SS19 SD0343 1533-AS06 1533-SS19 SD0344 1533-AS071533-SS19 SD0345 1533-AS08 1533-SS19 SD0346 1533-AS09 1533-SS19 SD03471533-AS10 1533-SS19 SD0348 1533-AS11 1533-SS19 SD0349 1533-AS121533-SS19 SD0350 1533-AS13 1533-SS19 SD0351 1533-AS14 1533-SS19 SD03521532-AS00 1532-SS00 SD0353 1532-AS01 1532-SS00 SD0354 1532-AS021532-SS00 SD0355 1532-AS03 1532-SS00 SD0356 1532-AS04 1532-SS00 SD03571532-AS05 1532-SS00 SD0358 1532-AS06 1532-SS00 SD0359 1532-AS071532-SS00 SD0360 1532-AS08 1532-SS00 SD0361 1532-AS09 1532-SS00 SD03621532-AS10 1532-SS00 SD0363 1532-AS11 1532-SS00 SD0364 1532-AS121532-SS00 SD0365 1532-AS13 1532-SS00 SD0366 1532-AS00 1532-SS01 SD03671532-AS01 1532-SS01 SD0368 1532-AS02 1532-SS01 SD0369 1532-AS031532-SS01 SD0370 1532-AS04 1532-SS01 SD0371 1532-AS05 1532-SS01 SD03721532-AS06 1532-SS01 SD0373 1532-AS07 1532-SS01 SD0374 1532-AS081532-SS01 SD0375 1532-AS09 1532-SS01 SD0376 1532-AS10 1532-SS01 SD03771532-AS11 1532-SS01 SD0378 1532-AS12 1532-SS01 SD0379 1532-AS131532-SS01 SD0380 1532-AS00 1532-SS02 SD0381 1532-AS01 1532-SS02 SD03821532-AS02 1532-SS02 SD0383 1532-AS03 1532-SS02 SD0384 1532-AS041532-SS02 SD0385 1532-AS05 1532-SS02 SD0386 1532-AS06 1532-SS02 SD03871532-AS07 1532-SS02 SD0388 1532-AS08 1532-SS02 SD0389 1532-AS091532-SS02 SD0390 1532-AS10 1532-SS02 SD0391 1532-AS11 1532-SS02 SD03921532-AS12 1532-SS02 SD0393 1532-AS13 1532-SS02 SD0394 1532-AS001532-SS03 SD0395 1532-AS01 1532-SS03 SD0396 1532-AS02 1532-SS03 SD03971532-AS03 1532-SS03 SD0398 1532-AS04 1532-SS03 SD0399 1532-AS051532-SS03 SD0400 1532-AS06 1532-SS03 SD0401 1532-AS07 1532-SS03 SD04021532-AS08 1532-SS03 SD0403 1532-AS09 1532-SS03 SD0404 1532-AS101532-SS03 SD0405 1532-AS11 1532-SS03 SD0406 1532-AS12 1532-SS03 SD04071532-AS13 1532-SS03 SD0408 1532-AS00 1532-SS04 SD0409 1532-AS011532-SS04 SD0410 1532-AS02 1532-SS04 SD0411 1532-AS03 1532-SS04 SD04121532-AS04 1532-SS04 SD0413 1532-AS05 1532-SS04 SD0414 1532-AS061532-SS04 SD0415 1532-AS07 1532-SS04 SD0416 1532-AS08 1532-SS04 SD04171532-AS09 1532-SS04 SD0418 1532-AS10 1532-SS04 SD0419 1532-AS111532-SS04 SD0420 1532-AS12 1532-SS04 SD0421 1532-AS13 1532-SS04 SD04221532-AS00 1532-SS05 SD0423 1532-AS01 1532-SS05 SD0424 1532-AS021532-SS05 SD0425 1532-AS03 1532-SS05 SD0426 1532-AS04 1532-SS05 SD04271532-AS05 1532-SS05 SD0428 1532-AS06 1532-SS05 SD0429 1532-AS071532-SS05 SD0430 1532-AS08 1532-SS05 SD0431 1532-AS09 1532-SS05 SD04321532-AS10 1532-SS05 SD0433 1532-AS11 1532-SS05 SD0434 1532-AS121532-SS05 SD0435 1532-AS13 1532-SS05 SD0436 1532-AS00 1532-SS06 SD04371532-AS01 1532-SS06 SD0438 1532-AS02 1532-SS06 SD0439 1532-AS031532-SS06 SD0440 1532-AS04 1532-SS06 SD0441 1532-AS05 1532-SS06 SD04421532-AS06 1532-SS06 SD0443 1532-AS07 1532-SS06 SD0444 1532-AS081532-SS06 SD0445 1532-AS09 1532-SS06 SD0446 1532-AS10 1532-SS06 SD04471532-AS11 1532-SS06 SD0448 1532-AS12 1532-SS06 SD0449 1532-AS131532-SS06 SD0450 1532-AS00 1532-SS07 SD0451 1532-AS01 1532-SS07 SD04521532-AS02 1532-SS07 SD0453 1532-AS03 1532-SS07 SD0454 1532-AS041532-SS07 SD0455 1532-AS05 1532-SS07 SD0456 1532-AS06 1532-SS07 SD04571532-AS07 1532-SS07 SD0458 1532-AS08 1532-SS07 SD0459 1532-AS091532-SS07 SD0460 1532-AS10 1532-SS07 SD0461 1532-AS11 1532-SS07 SD04621532-AS12 1532-SS07 SD0463 1532-AS13 1532-SS07 SD0464 1532-AS001532-SS08 SD0465 1532-AS01 1532-SS08 SD0466 1532-AS02 1532-SS08 SD04671532-AS03 1532-SS08 SD0468 1532-AS04 1532-SS08 SD0469 1532-AS051532-SS08 SD0470 1532-AS06 1532-SS08 SD0471 1532-AS07 1532-SS08 SD04721532-AS08 1532-SS08 SD0473 1532-AS09 1532-SS08 SD0474 1532-AS101532-SS08 SD0475 1532-AS11 1532-SS08 SD0476 1532-AS12 1532-SS08 SD04771532-AS13 1532-SS08 SD0478 1532-AS00 1532-SS09 SD0479 1532-AS011532-SS09 SD0480 1532-AS02 1532-SS09 SD0481 1532-AS03 1532-SS09 SD04821532-AS04 1532-SS09 SD0483 1532-AS05 1532-SS09 SD0484 1532-AS061532-SS09 SD0485 1532-AS07 1532-SS09 SD0486 1532-AS08 1532-SS09 SD04871532-AS09 1532-SS09 SD0488 1532-AS10 1532-SS09 SD0489 1532-AS111532-SS09 SD0490 1532-AS12 1532-SS09 SD0491 1532-AS13 1532-SS09 SD04921532-AS00 1532-SS10 SD0493 1532-AS01 1532-SS10 SD0494 1532-AS021532-SS10 SD0495 1532-AS03 1532-SS10 SD0496 1532-AS04 1532-SS10 SD04971532-AS05 1532-SS10 SD0498 1532-AS06 1532-SS10 SD0499 1532-AS071532-SS10 SD0500 1532-AS08 1532-SS10 SD0501 1532-AS09 1532-SS10 SD05021532-AS10 1532-SS10 SD0503 1532-AS11 1532-SS10 SD0504 1532-AS121532-SS10 SD0505 1532-AS13 1532-SS10 SD0506 1532-AS00 1532-SS11 SD05071532-AS01 1532-SS11 SD0508 1532-AS02 1532-SS11 SD0509 1532-AS031532-SS11 SD0510 1532-AS04 1532-SS11 SD0511 1532-AS05 1532-SS11 SD05121532-AS06 1532-SS11 SD0513 1532-AS07 1532-SS11 SD0514 1532-AS081532-SS11 SD0515 1532-AS09 1532-SS11 SD0516 1532-AS10 1532-SS11 SD05171532-AS11 1532-SS11 SD0518 1532-AS12 1532-SS11 SD0519 1532-AS131532-SS11 SD0520 1532-AS00 1532-SS12 SD0521 1532-AS01 1532-SS12 SD05221532-AS02 1532-SS12 SD0523 1532-AS03 1532-SS12 SD0524 1532-AS041532-SS12 SD0525 1532-AS05 1532-SS12 SD0526 1532-AS06 1532-SS12 SD05271532-AS07 1532-SS12 SD0528 1532-AS08 1532-SS12 SD0529 1532-AS091532-SS12 SD0530 1532-AS10 1532-SS12 SD0531 1532-AS11 1532-SS12 SD05321532-AS12 1532-SS12 SD0533 1532-AS13 1532-SS12 SD0534 1532-AS001532-SS13 SD0535 1532-AS01 1532-SS13 SD0536 1532-AS02 1532-SS13 SD05371532-AS03 1532-SS13 SD0538 1532-AS04 1532-SS13 SD0539 1532-AS051532-SS13 SD0540 1532-AS06 1532-SS13 SD0541 1532-AS07 1532-SS13 SD05421532-AS08 1532-SS13 SD0543 1532-AS09 1532-SS13 SD0544 1532-AS101532-SS13 SD0545 1532-AS11 1532-SS13 SD0546 1532-AS12 1532-SS13 SD05471532-AS13 1532-SS13 SD0548 1532-AS00 1532-SS14 SD0549 1532-AS011532-SS14 SD0550 1532-AS02 1532-SS14 SD0551 1532-AS03 1532-SS14 SD05521532-AS04 1532-SS14 SD0553 1532-AS05 1532-SS14 SD0554 1532-AS061532-SS14 SD0555 1532-AS07 1532-SS14 SD0556 1532-AS08 1532-SS14 SD05571532-AS09 1532-SS14 SD0558 1532-AS10 1532-SS14 SD0559 1532-AS111532-SS14 SD0560 1532-AS12 1532-SS14 SD0561 1532-AS13 1532-SS14 SD05621532-AS00 1532-SS15 SD0563 1532-AS01 1532-SS15 SD0564 1532-AS021532-SS15 SD0565 1532-AS03 1532-SS15 SD0566 1532-AS04 1532-SS15 SD05671532-AS05 1532-SS15 SD0568 1532-AS06 1532-SS15 SD0569 1532-AS071532-SS15 SD0570 1532-AS08 1532-SS15 SD0571 1532-AS09 1532-SS15 SD05721532-AS10 1532-SS15 SD0573 1532-AS11 1532-SS15 SD0574 1532-AS121532-SS15 SD0575 1532-AS13 1532-SS15 SD0576 1532-AS00 1532-SS16 SD05771532-AS01 1532-SS16 SD0578 1532-AS02 1532-SS16 SD0579 1532-AS031532-SS16 SD0580 1532-AS04 1532-SS16 SD0581 1532-AS05 1532-SS16 SD05821532-AS06 1532-SS16 SD0583 1532-AS07 1532-SS16 SD0584 1532-AS081532-SS16 SD0585 1532-AS09 1532-SS16 SD0586 1532-AS10 1532-SS16 SD05871532-AS11 1532-SS16 SD0588 1532-AS12 1532-SS16 SD0589 1532-AS131532-SS16 SD0590 1532-AS00 1532-SS17 SD0591 1532-AS01 1532-SS17 SD05921532-AS02 1532-SS17 SD0593 1532-AS03 1532-SS17 SD0594 1532-AS041532-SS17 SD0595 1532-AS05 1532-SS17 SD0596 1532-AS06 1532-SS17 SD05971532-AS07 1532-SS17 SD0598 1532-AS08 1532-SS17 SD0599 1532-AS091532-SS17 SD0600 1532-AS10 1532-SS17 SD0601 1532-AS11 1532-SS17 SD06021532-AS12 1532-SS17 SD0603 1532-AS13 1532-SS17 SD0604 1532-AS001532-SS18 SD0605 1532-AS01 1532-SS18 SD0606 1532-AS02 1532-SS18 SD06071532-AS03 1532-SS18 SD0608 1532-AS04 1532-SS18 SD0609 1532-AS051532-SS18 SD0610 1532-AS06 1532-SS18 SD0611 1532-AS07 1532-SS18 SD06121532-AS08 1532-SS18 SD0613 1532-AS09 1532-SS18 SD0614 1532-AS101532-SS18 SD0615 1532-AS11 1532-SS18 SD0616 1532-AS12 1532-SS18 SD06171532-AS13 1532-SS18 SD0618 1532-AS00 1532-SS19 SD0619 1532-AS011532-SS19 SD0620 1532-AS02 1532-SS19 SD0621 1532-AS03 1532-SS19 SD06221532-AS04 1532-SS19 SD0623 1532-AS05 1532-SS19 SD0624 1532-AS061532-SS19 SD0625 1532-AS07 1532-SS19 SD0626 1532-AS08 1532-SS19 SD06271532-AS09 1532-SS19 SD0628 1532-AS10 1532-SS19 SD0629 1532-AS111532-SS19 SD0630 1532-AS12 1532-SS19 SD0631 1532-AS13 1532-SS19 SD06321532-AS00 1532-SS20 SD0633 1532-AS01 1532-SS20 SD0634 1532-AS021532-SS20 SD0635 1532-AS03 1532-SS20 SD0636 1532-AS04 1532-SS20 SD06371532-AS05 1532-SS20 SD0638 1532-AS06 1532-SS20 SD0639 1532-AS071532-SS20 SD0640 1532-AS08 1532-SS20 SD0641 1532-AS09 1532-SS20 SD06421532-AS10 1532-SS20 SD0643 1532-AS11 1532-SS20 SD0644 1532-AS121532-SS20 SD0645 1532-AS13 1532-SS20 SD0646 1532-AS00 1532-SS21 SD06471532-AS01 1532-SS21 SD0648 1532-AS02 1532-SS21 SD0649 1532-AS031532-SS21 SD0650 1532-AS04 1532-SS21 SD0651 1532-AS05 1532-SS21 SD06521532-AS06 1532-SS21 SD0653 1532-AS07 1532-SS21 SD0654 1532-AS081532-SS21 SD0655 1532-AS09 1532-SS21 SD0656 1532-AS10 1532-SS21 SD06571532-AS11 1532-SS21 SD0658 1532-AS12 1532-SS21 SD0659 1532-AS131532-SS21 SD0660 1532-AS00 1532-SS22 SD0661 1532-AS01 1532-SS22 SD06621532-AS02 1532-SS22 SD0663 1532-AS03 1532-SS22 SD0664 1532-AS041532-SS22 SD0665 1532-AS05 1532-SS22 SD0666 1532-AS06 1532-SS22 SD06671532-AS07 1532-SS22 SD0668 1532-AS08 1532-SS22 SD0669 1532-AS091532-SS22 SD0670 1532-AS10 1532-SS22 SD0671 1532-AS11 1532-SS22 SD06721532-AS12 1532-SS22 SD0673 1532-AS13 1532-SS22 SD0674 1532-AS001532-SS23 SD0675 1532-AS01 1532-SS23 SD0676 1532-AS02 1532-SS23 SD06771532-AS03 1532-SS23 SD0678 1532-AS04 1532-SS23 SD0679 1532-AS051532-SS23 SD0680 1532-AS06 1532-SS23 SD0681 1532-AS07 1532-SS23 SD06821532-AS08 1532-SS23 SD0683 1532-AS09 1532-SS23 SD0684 1532-AS101532-SS23 SD0685 1532-AS11 1532-SS23 SD0686 1532-AS12 1532-SS23 SD06871532-AS13 1532-SS23 SD0688 1532-AS00 1532-SS24 SD0689 1532-AS011532-SS24 SD0690 1532-AS02 1532-SS24 SD0691 1532-AS03 1532-SS24 SD06921532-AS04 1532-SS24 SD0693 1532-AS05 1532-SS24 SD0694 1532-AS061532-SS24 SD0695 1532-AS07 1532-SS24 SD0696 1532-AS08 1532-SS24 SD06971532-AS09 1532-SS24 SD0698 1532-AS10 1532-SS24 SD0699 1532-AS111532-SS24 SD0700 1532-AS12 1532-SS24 SD0701 1532-AS13 1532-SS24 SD07021532-AS14 1532-SS00 SD0703 1532-AS15 1532-SS00 SD0704 1532-AS161532-SS00 SD0705 1532-AS17 1532-SS00 SD0706 1532-AS18 1532-SS00 SD07071532-AS19 1532-SS00 SD0708 1532-AS20 1532-SS00 SD0709 1532-AS211532-SS00 SD0710 1532-AS22 1532-SS00 SD0711 1532-AS23 1532-SS00 SD07121532-AS24 1532-SS00 SD0713 1532-AS25 1532-SS00 SD0714 1532-AS261532-SS00 SD0715 1532-AS27 1532-SS00

In some embodiments, an LPA RNAi agent comprises an antisense strandcomprising the nucleotide sequence of SEQ ID NO:1242(TCGUAUAACAAUAAGGGGC). In some embodiments, an LPA RNAi agent comprisesan antisense strand comprising the nucleotide sequence of SEQ ID NO:1244(UCGUAUAACAAUAAGGGG). In some embodiments, an LPA RNAi agent comprisesan antisense strand comprising the nucleotide sequence of SEQ ID NO:1246(UCGUAUAACAAUAAGGG). In some embodiments, an LPA RNAi agent comprises anantisense strand comprising the nucleotide sequence of SEQ ID NO:1248(TGAGAAUGAGCCUCGAUAA). In some embodiments, an LPA RNAi agent comprisesan antisense strand comprising the nucleotide sequence of SEQ ID NO:1250(UGAGAAUGAGCCUCGAUA). In some embodiments, an LPA RNAi agent comprisesan antisense strand comprising the nucleotide sequence of SEQ ID NO:1252(UGAGAAUGAGCCUCGAU). In some embodiments, an LPA RNAi agent comprises anantisense strand comprising the nucleotide sequence of SEQ ID NO:1254(UGUAUAACAAUAAGGGG). In some embodiments, an LPA RNAi agent comprises anantisense strand comprising the nucleotide sequence of SEQ ID NO: 1280(CGUAUAACAAUAAGGGGC). In some embodiments, an LPA RNAi agent comprisesan antisense strand comprising the nucleotide sequence of SEQ ID NO:1281(GAGAAUGAGCCUCGAUAA). In some embodiments, an LPA RNAi agent comprisesan antisense strand comprising the nucleotide sequence of SEQ ID NO:1282(UCGUAUAACAAUAAGGGGC). In some embodiments, an LPA RNAi agent comprisesan antisense strand comprising the nucleotide sequence of SEQ ID NO:1283 (UGAGAAUGAGCCUCGAUAA). In some embodiments, one or more of thenucleotides is modified.

In some embodiments, an LPA RNAi agent comprises a sense strandcomprising the nucleotide sequence of SEQ ID NO:1243(GCCCCUUAUUGUUAUACGA). In some embodiments, an LPA RNAi agent comprisesa sense strand comprising the nucleotide sequence of SEQ ID NO:1245(CCCCUUAUUGUUAUACGA). In some embodiments, an LPA RNAi agent comprises asense strand comprising the nucleotide sequence of SEQ ID NO:1247(CCCUUAUUGUUAUACGA). In some embodiments, an LPA RNAi agent comprises asense strand comprising the nucleotide sequence of SEQ ID NO: 1249(UUAUCGAGGCUCAUUCUCA). In some embodiments, an LPA RNAi agent comprisesa sense strand comprising the nucleotide sequence of SEQ ID NO:1251(UAUCGAGGCUCAUUCUCA). In some embodiments, an LPA RNAi agent comprises asense strand comprising the nucleotide sequence of SEQ ID NO:1253(AUCGAGGCUCAUUCUCA). In some embodiments, an LPA RNAi agent comprises asense strand comprising the nucleotide sequence of SEQ ID NO: 1255(CCCCUUAUUGUUAUACA). In some embodiments, an LPA RNAi agent comprises asense strand comprising the nucleotide sequence of SEQ ID NO: 1284(GCCCCUUAUUGUUAUACG). In some embodiments, an LPA RNAi agent comprises asense strand comprising the nucleotide sequence of SEQ ID NO: 1285(UUAUCGAGGCUCAUUCUC). In some embodiments, one or more of thenucleotides is modified.

In some embodiments, an LPA RNAi agent comprises an antisense strandcomprising the nucleotide sequence of SEQ ID NO:1242 and a sense strandcomprising the nucleotide sequence of SEQ ID NO:1243. In someembodiments, an LPA RNAi agent comprises an antisense strand comprisingthe nucleotide sequence of SEQ ID NO: 1244 and a sense strand comprisingthe nucleotide sequence of SEQ ID NO: 1245. In some embodiments, an LPARNAi agent comprises an antisense strand comprising the nucleotidesequence of SEQ ID NO: 1246 and a sense strand comprising the nucleotidesequence of SEQ ID NO:1247. In some embodiments, an LPA RNAi agentcomprises an antisense strand comprising the nucleotide sequence of SEQID NO: 1248 and a sense strand comprising the nucleotide sequence of SEQID NO: 1249. In some embodiments, an LPA RNAi agent comprises anantisense strand comprising the nucleotide sequence of SEQ ID NO: 1250and a sense strand comprising the nucleotide sequence of SEQ ID NO:1251.In some embodiments, an LPA RNAi agent comprises an antisense strandcomprising the nucleotide sequence of SEQ ID NO:1252 and a sense strandcomprising the nucleotide sequence of SEQ ID NO: 1253. In someembodiments, an LPA RNAi agent comprises an antisense strand comprisingthe nucleotide sequence of SEQ ID NO: 1254 and sense strand comprisingthe nucleotide sequence of SEQ ID NO: 1255. In some embodiments, an LPARNAi agent comprises an antisense strand comprising the nucleotidesequence of SEQ ID NO:1280 and a sense strand comprising the nucleotidesequence of SEQ ID NO: 1284. In some embodiments, an LPA RNAi agentcomprises an antisense strand comprising the nucleotide sequence of SEQID NO: 1281 and a sense strand comprising the nucleotide sequence of SEQID NO: 1285. In some embodiments, an LPA RNAi agent comprises anantisense strand comprising the nucleotide sequence of SEQ ID NO: 1282and a sense strand comprising the nucleotide sequence of SEQ ID NO:1259. In some embodiments, an LPA RNAi agent comprises an antisensestrand comprising the nucleotide sequence of SEQ ID NO: 1283 and a sensestrand comprising the nucleotide sequence of SEQ ID NO: 1249. In someembodiments, one or more of the nucleotides is modified.

In some embodiments, an LPA RNAi agent comprises an antisense strandcomprising the nucleotide sequence of SEQ ID NO. 156, 164, or 188. Insome embodiments, an LPA RNAi agent comprises a sense strand comprisingthe nucleotide sequence of SEQ ID NO. 310, 357, 384, or 376. In someembodiments, an LPA RNAi agent comprises an antisense strand and a sensestrand comprising the nucleotide sequences of SEQ ID NOs: 156/310, SEQID NOs: 164/357, SEQ ID NOs: 188/384, SEQ ID NOs: 164/376, or SEQ IDNOs: 164/384. In some embodiments, one or more of the nucleotides ismodified.

In some embodiments, an LPA RNAi agent comprises an antisense strandcomprising the nucleotide sequence of SEQ ID NO. 637, 709, 790, 787, or788. In some embodiments, an LPA RNAi agent comprises a sense strandcomprising the nucleotide sequence of SEQ ID NO: 1132, 1135, 1189, 1191,or 1186. In some embodiments, an LPA RNAi agent comprises an antisensestrand and a sense strand comprising the nucleotide sequences of SEQ IDNOs:637/1132, SEQ ID NOs:709/1135, SEQ ID NOs:790/1189. SEQ IDNOs:787/1191, or SEQ ID NOs: 788/1186.

In some embodiments, an LPA RNAi agent comprises SEQ ID NO. 637, 709,790, 787, or 788. In some embodiments, an LPA RNAi agent comprises SEQID NO:1132, 1135, 1189, 1191, or 1186. In some embodiments, an LPA RNAiagent comprises SEQ ID NOs:637/1132, SEQ ID NOs:709/1135, SEQ IDNOs:790/1189, SEQ ID NOs:787/1191, or SEQ ID NOs:788/1186.

In some embodiments, an LPA RNAi agent consists of SEQ ID NO. 637, 709,790, 787, or 788. In some embodiments, an LPA RNAi agent consists of SEQID NO:1132, 1135, 1189, 1191, or 1186. In some embodiments, an LPA RNAiagent consists of SEQ ID NOs:637/1132, SEQ ID NOs:709/1135, SEQ IDNOs:790/1189, SEQ ID NOs:787/1191, or SEQ ID NOs:788/186.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the nucleotide sequences of any of the antisensestrand/sense strand duplexes of Table 3A or 3B.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the nucleotide sequences of any of the antisensestrand/sense strand duplexes of Table 3A or 3B, and further comprises anasialoglycoprotein receptor ligand targeting group.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the nucleotide sequences of any of the antisensestrand/sense strand duplexes of Table 3A or 3B, and further comprises atargeting group selected from the group consisting of (C11¬PEG3¬NAG3),(C11-PEG3-NAG3), (C6-PEG4-NAG3), (NAG 3), (NAG4), (NAG3¬AA2),(NAG3-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26),(NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13),(NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the modified nucleotide sequences of any of theantisense strand/sense strand duplexes of Table 3A or 3B.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the modified nucleotide sequences of any of theantisense strand/sense strand duplexes of Table 3A or 3B, and furthercomprises an asialoglycoprotein receptor ligand targeting group.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the modified nucleotide sequences of any of theantisense strandsense strand duplexes of Table 3A or 3B, and furthercomprises a targeting group selected from the group consisting of(C11-PEG3-NAG3), (C11-PEG3-NAG3), (C6-PEG4-NAG3), (NAG 3), (NAG4),(NAG3-AA2), (NAG3-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s,(NAG26), (NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13),(NAG3 s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

In some embodiments, an LPA RNAi agent comprises any of the duplexes ofTable 3A or 3B.

In some embodiments, an LPA RNAi agent consists of any of the duplexesof Table 3A or 3B.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the nucleotide sequences AD03460, AD03536,AD03581, AD03583, AD3847, or AD04110.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the nucleotide sequences AD03460, AD03536,AD03581, AD03583, AD3847, or AD04110, and further comprises anasialoglycoprotein receptor ligand targeting group.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the nucleotide sequences AD03460, AD03536,AD03581, AD03583, AD3847, or AD04110, and further comprises a targetinggroup selected from the group consisting of (C11-PEG3-NAG3),(C11-PEG3-NAG3), (C6-PEG4-NAG3), (NAG 3), (NAG4), (NAG3-AA2),(NAG3-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26),(NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13),(NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the modified nucleotide sequences AD03460,AD03536, AD03581, AD03583, AD3847, or AD04110.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the modified nucleotide sequences AD03460,AD03536, AD03581, AD03583, AD3847, or AD04110, and further comprises anasialoglycoprotein receptor ligand targeting group.

In some embodiments, an LPA RNAi agent comprises an antisense strand anda sense strand having the modified nucleotide sequences AD03460,AD03536, AD03581, AD03583, AD3847, or AD04110, and further comprises atargeting group selected from the group consisting of (C11-PEG3-NAG3),(C11-PEG3-NAG3), (C6-PEG4-NAG3), (NAG3), (NAG4), (NAG3-AA2),(NAG3-Palm), (NAG13), (NAG18), (NAG24), (NAG25), (NAG25)s, (NAG26),(NAG27), (NAG28), (NAG29), (NAG30), (NAG30)s, (NAG31), (NAG13),(NAG31s), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), and (NAG37).

In some embodiments, an LPA RNAi agent comprises AD03460, AD03536,AD03581, AD03583, AD3847, or AD04110.

In some embodiments, an LPA RNAi agent consists of AD03460, AD03536,AD03581, AD03583, AD3847, or AD04110.

Non-Nucleotide Group

In some embodiments, an LPA RNAi agent contains or is conjugated to oneor more non-nucleotide groups including, but not limited to a targetinggroup, linking group, delivery polymer, or a delivery vehicle. Thenon-nucleotide group can enhance targeting, delivery or attachment ofthe RNAi agent. Examples of targeting groups and linking groups areprovided in Table 4. The non-nucleotide group can be covalently linkedto the 3′ and/or 5′ end of either the sense strand and/or the antisensestrand. In some embodiments, an LPA RNAi agent contains a non-nucleotidegroup linked to the 3′ and/or 5′ end of the sense strand. In someembodiments a non-nucleotide group is linked to the 5′ end of an LPARNAi agent sense strand. A non-nucleotide group may linked directly orindirectly to the RNAi agent via a linker/linking group. In someembodiments a non-nucleotide group is linked to the RNAi agent via alabile, cleavable, or reversible bond or linker.

In some embodiments, a non-nucleotide group enhances the pharmacokineticor biodistribution properties of an RNAi agent or conjugate to which itis attached to improve cell- or tissue-specific distribution andcell-specific uptake of the conjugate. In some embodiments, anon-nucleotide group enhances endocytosis of the RNAi agent.

Targeting Group

A targeting group can be monovalent, divalent, trivalent, tetravalent,or have higher valency. Representative targeting groups include, withoutlimitation, compounds with affinity to cell surface molecule, cellreceptor ligands, hapten, antibodies, monoclonal antibodies, antibodyfragments, and antibody mimics with affinity to cell surface molecules.In some embodiments, a targeting group is linked to an RNAi agent usinga linker, such as a PEG linker or one, two, or three abasic and/orribitol groups. In some embodiments, a targeting group comprises agalactose cluster.

The LPA RNAi agents described herein may be synthesized having areactive group, such as an amine group, at the 5′-terminus. The reactivegroup may be used to subsequently attach a targeting moiety usingmethods typical in the art.

In some embodiments, a targeting group comprises an asialoglycoproteinreceptor ligand. In some embodiments, an asialoglycoprotein receptorligand includes or consists of one or more galactose derivatives orgalactose clusters. As used herein, the term galactose derivativeincludes both galactose and derivatives of galactose having affinity forthe asialoglycoprotein receptor that is equal to or greater than that ofgalactose. Galactose derivatives include, but are not limited to:galactose, galactosamine, N-formylgalactosamine, N-acetyl-galactosamine,N-propionyl-galactosamine, N-n-butanoyl-galactosamine, andN-iso-butanoylgalactos-amine (see for example: Iobst. S. T. andDrickamer, K. J. B. C. 1996, 271, 6686). Galactose derivatives andgalactose clusters that are useful for in vivo targeting ofoligonucleotides and other molecules to the liver are known in the art(see, for example, Baenziger and Fiete, 1980, Cell, 22, 611-620;Connolly et al., 1982, J. Biol. Chem., 257, 939-945). Galactosederivatives have been used to target molecules to hepatocytes in viwthrough their binding to the asialoglycoprotein receptor (ASGPr)expressed on the surface of hepatocytes. Binding of ASGPr ligands to theASGPr(s) facilitates cell-specific targeting to hepatocytes andendocytosis of the molecule into hepatocytes. The galactose cluster maybe attached to the 3′ or 5′ end of the RNAi polynucleotide using methodsknown in the art.

As used herein, a galactose cluster comprises a molecule having two tofour terminal galactose derivatives. A terminal galactose derivative isattached to a molecule through its C-1 carbon. In some embodiments, thegalactose cluster is a galactose derivative trimer, tri-antennarygalactose derivative, or tri-valent galactose derivative. In someembodiments, the galactose cluster is comprises N-acetylgalactosamines(GalNAc). In some embodiments, the galactose cluster comprises atri-valent N-acetyl-galactosamine. In some embodiments, the galactosecluster is a galactose derivative tetramer, tetra-antennary galactosederivative, or tetra-valent galactose derivative. In some embodiments,the galactose cluster comprises a tetra-valent N-acetyl-galactosamine.

As used herein, a galactose trimer contains three galactose derivatives,each linked to a central branch point. As used herein, a galactosederivative tetramer contains four galactose derivatives, each linked toa central branch point. The galactose derivatives can be attached to thecentral branch point through the C-1 carbons of the saccharides. In someembodiments, the galactose derivatives are linked to the branch pointvia linkers or spacers. In some embodiments, the linker or spacer is aflexible hydrophilic spacer, such as a PEG group (see, for example, U.S.Pat. No. 5,885,968; Biessen et al. J. Med. Chem. 1995 Vol. 39 p.1538-1546). In some embodiments, the PEG spacer is a PEG3 spacer. Thebranch point can be any small molecule which permits attachment of thethree galactose derivatives and further permits attachment of the branchpoint to the RNAi agent. An example of branch point group is a di-lysineor di-glutamate. Attachment of the branch point to the RNAi agent canoccur through a linker or spacer. In some embodiments, the linker orspacer comprises a flexible hydrophilic spacer, such as, but not limitedto: a PEG spacer. In some embodiments, a PEG spacer is a PEG₃ spacer(three ethylene units). In other embodiments, the PEG spacer has 1 to 20ethylene units (PEG₁ to PEG₂₀). In some embodiments, a galactosederivative comprises an N-acetylgalactosamine (GalNAc or NAG). In someembodiments, the galactose cluster is comprised of a galactosederivative tetramer, which can be, for example, anN-acetyl-galactosamine tetramer.

In some embodiments, pharmaceutical compositions for delivering an LPARNAi agent to a liver cell in vivo are described. Such pharmaceuticalcompositions can include, for example, an LPA RNAi agent conjugated to agalactose cluster. In some embodiments, the galactose cluster iscomprised of a galactose derivative trimer, which can be, for example,an N-acetyl-galactosamine trimer, or galactose derivative tetramer,which can be, for example, an N-acetyl-galactosamine tetramer.

Targeting groups include, but are not limited to, (Chol-TEG),(TEG-Chol), (C11-PEG3-NAG3), (C_(m)-PEG_(n)-NAG3), (C_(x)-PEG_(z)-NAG3),(NAG 3), (NAG4), (NAG3-AA2), (NAG3-Palm), (NAG13), (NAG18), (NAG24),(NAG25), (NAG25)s, (NAG26), (NAG27), (NAG28), (NAG29), (NAG30),(NAG30)s, (NAG31), (NAG13), (NAG31s), (NAG32), (NAG33), (NAG34),(NAG35), (NAG36), and (NAG37).

Linking Group

In some embodiments, a linking group is conjugated to the RNAi agent.The linking group facilitates covalent linkage of the agent to atargeting group or delivery polymer or delivery vehicle. The linkinggroup can be linked to the 3′ or the 5′ end of the RNAi agent sensestrand or antisense strand. In some embodiments, the linking group islinked to the RNAi agent sense strand. In some embodiments, the linkinggroup is conjugated to the 5′ or 3′ end of an RNAi agent sense strand.In some embodiments a linking group is conjugated to the 5′ end of anRNAi agent sense strand. Examples of linking groups, include, but arenot limited to: Alk-SMPT-C6, Alk-SS-C6, DBCO-TEG, Me-Alk-SS-C6, andC6-SS-Alk-Me, reactive groups such a primary amines and alkynes, alkylgroups, abasic ribose, ribitol, and/or PEG groups.

A linker or linking group is a connection between two atoms that linksone chemical group (such as an RNAi agent) or segment of interest toanother chemical group (such as a targeting group or delivery polymer)or segment of interest via one or more covalent bonds. A labile linkagecontains a labile bond. A linkage may optionally include a spacer thatincreases the distance between the two joined atoms. A spacer mayfurther add flexibility and/or length to the linkage. Spacers mayinclude, but are not be limited to, alkyl groups, alkenyl groups,alkynyl groups, aryl groups, aralkyl groups, aralkenyl groups, andaralkynyl groups; each of which can contain one or more heteroatoms,heterocycles, amino acids, nucleotides, and saccharides. Spacer groupsare well known in the art and the preceding list is not meant to limitthe scope of the description.

Linking groups include, but are not limited to, Alkyl, PEG,(C6-PEG_(n)-Alk), (C_(n)-SMPT-Alk), and (C_(n)—SS-Alk-Me).

Any of the LPA RNAi agents listed in Tables 2A and 2B which contains a3′ or 5′ targeting group or linking group, may alternatively contain no3′ or 5′ targeting group or linking group, or may contain a different 3′or 5′ targeting group or linking group including, but not limited to,those depicted in Table 4. Any of the LPA RNAi agent nucleotidesequences listed in Tables 1, 2A and 2B, whether modified or unmodified,may contain 3′ or 5′ targeting group or linking group, including, butnot limited to, those depicted in Table 4. Any of the LPA RNAi agentduplexes listed in Tables 3A and 3B, whether modified or unmodified, mayfurther comprise a targeting group or linking group, including, but notlimited to, those depicted in Table 4, and the targeting group orlinking group may be attached to the 3′ or 5′ terminus of either thesense strand or the antisense strand of the LPA RNAi agent duplex.

TABLE 4 Structures representing various modified nucleotides, targetinggroups, and linking groups.

In each of the above structures, NAG comprises an N-Acetyl-Galactosamineor another ASGPR ligand. Each (NAGx) may be attached to an LPA RNAiagent via a phosphate group (as in (NAG25), (NAG30), and (NAG31)), or aphosphorothioate group, (as is (NAG25)s, (NAG30)s, and (NAG31)s), oranother linking group. Alternatively, other linking groups known in theart may be used.

Delivery Vehicles

In some embodiments, a delivery vehicle may be used to deliver an RNAiagent to a cell or tissue. A delivery vehicle is a compound thatimproves delivery of the RNAi agent to a cell or tissue. A deliveryvehicle can include, or consist of, but is not limited to: a polymer,such as an amphipathic polymer, a membrane active polymer, a peptide, amelittin peptide, a melittin-like peptide (MLP), a lipid, a reversiblymodified polymer or peptide, or a reversibly modified membrane activepolyamine.

In some embodiments, the RNAi agents can be combined with lipids,nanoparticles, polymers, liposomes, micelles, DPCs or other deliverysystems available in the art. The RNAi agents can also be chemicallyconjugated to targeting groups, lipids (including, but not limited tocholesterol and cholesteryl derivatives), nanoparticles, polymers,liposomes, micelles, DPCs (see, for example WO 2000/053722, WO2008/0022309, WO 2011/104169, and WO 2012/083185, WO 2013/032829, WO2013/158141, each of which is incorporated herein by reference), orother delivery systems available in the art.

Pharmaceutical Compositions

Described herein are methods for delivering LPA RNAi agents to livercells in a mammal in vivo. In some embodiments, a delivery vehicle maybe used. A delivery vehicle is a compound which improves delivery of theRNAi agent to the cell. A delivery vehicle can be, but is not limitedto: a polymer, such as an amphipathic polymer, membrane active polymer,a peptide, such as a melittin or melittin-like peptide, a reversiblymodified polymer or peptide, or a lipid.

In some embodiments, an LPA RNAi agent is linked to a targeting ligandthat comprises an asialoglycoprotein ligand. In some embodiments, an LPARNAi agent is linked to a targeting ligand that comprises or consists ofa galactose cluster.

An LPA RNAi agent can be used to inhibit expression of LPA in a cell,group of cells, or a tissue, e.g., in a subject. In some embodiments, anLPA RNAi agent is used to formulate a composition, i.e. a pharmaceuticalcomposition or medicament, for administering to a subject. As usedherein, a pharmaceutical composition or medicament comprises apharmacologically effective amount of at least one of the described LPARNAi agents and one or more pharmaceutically acceptable excipients.Pharmaceutically acceptable excipients (excipients) are substances otherthan the Active Pharmaceutical ingredient (API, therapeutic product,e.g., LPA RNAi agent) that have been appropriately evaluated for safetyand are intentionally included in the drug delivery system. Excipientsdo not exert or are not intended to exert a therapeutic effect at theintended dosage. Excipients may act to a) aid in processing of the drugdelivery system during manufacture, b) protect, support or enhancestability, bioavailability or patient acceptability of the API, c)assist in product identification, and/or d) enhance any other attributeof the overall safety, effectiveness, of delivery of the API duringstorage or use. A pharmaceutically acceptable excipient may or may notbe an inert substance.

Excipients include, but are not limited to: absorption enhancers,anti-adherents, anti-foaming agents, anti-oxidants, binders, binders,buffering agents, carriers, coating agents, colors, delivery enhancers,delivery polymers, dextran, dextrose, diluents, disintegrants,emulsifiers, extenders, fillers, flavors, glidants, humectants,lubricants, oils, polymers, preservatives, saline, salts, solvents,sugars, suspending agents, sustained release matrices, sweeteners,thickening agents, tonicity agents, vehicles, water-repelling agents,and wetting agents.

A pharmaceutical composition can contain other additional componentscommonly found in pharmaceutical compositions. Such additionalcomponents include, but are not limited to: anti-pruritics, astringents,local anesthetics, or anti-inflammatory agents (e.g., antihistamine,diphenhydramine, etc.). It is also envisioned that cells, tissues orisolated organs that express or comprise the herein defined RNAi agentsmay be used as “pharmaceutical compositions”. As used herein,“pharmacologically effective amount,” “therapeutically effectiveamount,” or simply “effective amount” refers to that amount of an RNAiagent to produce the intended pharmacological, therapeutic or preventiveresult.

In some embodiments, a described LPA RNAi agent is combined one or moreadditional therapeutics or treatments including, but not limited to: asecond LPA RNAi agent or other RNAi agent, a small molecule drug, anantibody, an antibody fragment, and/or a vaccine. Examples of additionaltherapeutics include, but are not limited to, HMg Co-A reductaseinhibitors (statins), ezetimibe, PCSK-9 inhibitors, CTEP inhibitors,therapies targeting ANGPTL3, therapies targeting APOC3, and niacin.

The described RNAi agents and pharmaceutical compositions comprising LPARNAi agents disclosed herein may be packaged or included in a kit,container, pack, or dispenser. The LPA RNAi agents and pharmaceuticalcompositions comprising said LPA RNAi agents may be packaged inpre-filled syringes or vials.

In some embodiments, pharmaceutical compositions comprising at least oneof the described LPA RNAi agents are contemplated. These pharmaceuticalcompositions are useful in the inhibition of the expression of the LPAgene in a cell, a tissue, or an organism. In some embodiments, thedescribed pharmaceutical compositions are used to treat a subject havinga disease, condition, or disorder that would benefit from reduction orinhibition in LPA expression. In some embodiments, the describedpharmaceutical compositions are used to treat a subject at risk ofdeveloping a disease, condition, or disorder that would benefit fromreduction or inhibition in LPA expression. Diseases, conditions, ordisorders that would benefit from reduction or inhibition in LPAexpression include, but are not limited to: Berger's disease, peripheralartery disease, coronary artery disease, metabolic syndrome, acutecoronary syndrome, aortic valve stenosis, aortic valve regurgitation,aortic dissection, retinal artery occlusion, cerebrovascular disease,mesenteric ischemia, superior mesenteric artery occlusion, renal arterystenosis, stable/unstable angina, acute coronary syndrome, heterozygousor homozygous familial hypercholesterolemia,hyperapobetalipoproteinemia, cerebrovascular atherosclerosis,cerebrovascular disease, and venous thrombosis. In some embodiments, thesubject is a mammal, including, but not limited to, a human patient.

Cells, tissues, and non-human organisms that include at least one of theLPA RNAi agents described herein is contemplated. The cell, tissue, ornon-human organism is made by delivering the RNAi agent to the cell,tissue, or non-human organism by any means available in the art. In someembodiments, the cell is a mammalian cell, including, but not limitedto, a human cell. The cell, tissue, or non-human organisms are usefulfor research or as research tools (e.g., drug testing or diagnoses).

Method of Treatment

In some embodiments, the LPA RNAi agents described herein are used totreat a subject having a disease, condition, or disorder or at risk ofhaving a disease, condition, or disorder that would benefit fromreduction or inhibition in LPA expression. Treatment of a subject thatwould benefit from a reduction and/or inhibition of LPA gene expressionincludes therapeutic and/or prophylactic treatment. Examples ofdiseases, conditions, or disorders, include, but not limited to:Berger's disease, peripheral artery disease, coronary artery disease,metabolic syndrome, acute coronary syndrome, aortic valve stenosis,aortic valve regurgitation, aortic dissection, retinal artery occlusion,cerebrovascular disease, mesenteric ischemia, superior mesenteric arteryocclusion, renal artery stenosis, stable/unstable angina, acute coronarysyndrome, heterozygous or homozygous familial hypercholesterolemia,hyperapobetalipoproteinemia, cerebrovascular atherosclerosis,cerebrovascular disease, and venous thrombosis. In some embodiments, themethod comprises administering a composition, such as a pharmaceuticalcomposition, comprising an LPA RNAi agent described herein to a mammalto be treated.

In some embodiments, a therapeutically effective amount of one or moreof the described LPA RNAi agents is administered to a subject, therebyinhibiting expression of LPA in the subject (e.g., an amount effectiveto inhibit expression of LPA in the subject). In some embodiments, oneor more of the LPA RNAi agents described herein are used to treat asubject having a disease or disorder that would benefit from reductionor inhibition in LPA expression. In some embodiments, the described LPARNAi agents are used to treat or prevent at least one symptom in asubject having a disease or disorder that would benefit from reductionor inhibition in LPA expression. The subject is administered atherapeutically effective amount of any one or more of the describedRNAi agents thereby treating the symptom. In some embodiments, thesubject is administered a prophylactically effective amount of any oneor more of the described RNAi agents thereby preventing the at least onesymptom.

In some embodiments, an LPA RNAi agent is used to treat or manage aclinical presentation wherein a subject in need of such treatment,prevention, or management is administered a therapeutically orprophylactically effective amount of one or more of the LPA RNAi agentsor LPA RNAi agent-containing compositions described herein. In someembodiments, the method comprises administering a composition comprisingan LPA RNAi agent described herein to a mammal to be treated.

In some embodiments, the methods further comprise the step ofadministering a second therapeutic or treatment. In some embodiments,the second therapeutic is another LPA RNAi agent (e.g., a LPA RNAi agentwhich targets a different sequence within the LPA target). In otherembodiments, the second therapeutic can be selected from the groupcomprising: small molecule drug, antibody, antibody fragment, andvaccine.

The route of administration is the path by which an RNAi agent isbrought into contact with the body. In general, methods of administeringdrugs and nucleic acids for treatment of a subject are well known in theart and can be applied to administration of the compositions describedherein. The compounds described herein can be administered via anysuitable route in a preparation appropriately tailored to the particularroute. Thus, the compounds described herein can be administered byinjection, for example, intravenously, intramuscularly,intracutaneously, subcutaneously, or intraperitoneally.

In some embodiments, the LPA RNAi agents or compositions describedherein can be delivered to a cell, group of cells, tissue, or subjectusing oligonucleotide delivery technologies known in the art. Ingeneral, any suitable method recognized in the art for delivering anucleic acid molecule (in vitro or in vivo) can be adapted for use withan LPA RNAi agent described herein. For example, delivery can be bylocal administration, (e.g., direct injection, implantation, or topicaladministering), systemic administration, or subcutaneous, intravenous,oral, intraperitoneal, or parenteral routes, including intracranial(e.g., intraventricular, intraparenchymal and intrathecal),intramuscular, transdermal, airway (aerosol), nasal, rectal, or topical(including buccal and sublingual) administration, In certainembodiments, the compositions are administered by subcutaneous orintravenous infusion or injection.

In some embodiments, the RNAi agents can be combined with lipids,nanoparticles, polymers, liposomes, micelles, DPCs or other deliverysystems available in the art. The RNAi agents can also be chemicallyconjugated to targeting groups, lipids (including, but not limited tocholesterol and cholesteryl derivatives), nanoparticles, polymers,liposomes, micelles, DPCs (see e.g., WO 2000/053722, WO 2008/0022309, WO2011/104169, and WO 2012/083185, each of which is incorporated herein byreference), or other delivery systems available in the art. An LPA RNAiagent can be conjugated to a delivery polymer. In some embodiments, thedelivery polymer is a reversibly masked/modified amphipathic membraneactive polyamine.

Inhibition of Expression

As used herein, the terms “silence,” “reduce,” “inhibit,”“down-regulate,” or “knockdown gene expression,” when referring to anLPA gene, mean that the expression of the gene, as measured by the levelof RNA transcribed from the gene or the level of polypeptide, protein,or protein subunit translated from the mRNA in a cell, group of cells,or tissue, in which the LPA gene is transcribed, is reduced when thecell, group of cells, or tissue, is treated with the described LPA RNAiagents as compared to a second cell, group of cells, or tissue that hasor has not been so treated or compared to the same cell, group of cells,or tissue, prior to administration of the LPA RNAi agent.

In some embodiments, the gene expression level and/or mRNA level of LPAin a subject to whom a described LPA RNAi agent is administered isreduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% relative to thesubject prior to being administered the LPA RNAi agent or to a subjectnot receiving the LPA RNAi agent. The gene expression level and/or mRNAlevel in the subject may be reduced in a cell, group of cells, and/ortissue of the subject. In some embodiments, the protein level of LPA ina subject to whom a described LPA RNAi agent has been administered isreduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90, 95%, or 98% relative to thesubject prior to being administered the LPA RNAi agent or to a subjectnot receiving the LPA RNAi agent. The protein level in the subject maybe reduced in a cell, group of cells, tissue, blood, and/or other fluidof the subject. A reduction in gene expression, mRNA, or protein levelscan be assessed by any methods known in the art. Reduction or decreasein LPA mRNA level and/or protein level are collectively referred toherein as a reduction or decrease in LPA or inhibiting or reducing theexpression of LPA.

Introducing into a cell, when referring to an RNAi agent, meansfunctionally delivering the RNAi agent into the cell. By functionaldelivery, it is meant that the RNAi agent is delivered to the cell andhas the expected biological activity, (e.g., sequence-specificinhibition of gene expression).

Cells and Tissues and Non-Human Organisms

Cells, tissues, and non-human organisms that include at least one of theLPA RNAi agents described herein is contemplated. The cell, tissue, ornon-human organism is made by delivering the RNAi agent to the cell,tissue, or non-human organism.

The above provided embodiments and items are now illustrated with thefollowing, non-limiting examples.

EXAMPLES Example 1. RNAi Agent Synthesis

A) Synthesis.

LPA RNAi agents were synthesized according to phosphoramidite technologyon solid phase used in oligonucleotide synthesis. Depending on the scaleeither a MerMade96E (Bioautomation) or a MerMade12 (Bioautomation) wasused. Syntheses were performed on a solid support made of controlledpore glass (CPG, 500 Å or 600 Å, obtained from Prime Synthesis, Aston,Pa., USA). All DNA, 2′-modified RNA, and UNA phosphoramidites werepurchased from Thermo Fisher Scientific (Milwaukee, Wis., USA).Specifically, the following 2′-O-Methyl phosphoramidites were used:(5′-O-dimethoxytrityl-N⁶-benzoyl)-2′-O-methyl-adenosine-3′-O-(2-cyanoethyl-N,N-diisopropyl-amino)phosphoramidite,5′-O-dimethoxy-trityl-N⁴-(acetyl)-2′-O-methyl-cytidine-3′-O-(2-cyanoethyl-N,N-diisopropyl-amino)phosphoramidite,(5′-O-dimethoxytrityl-N²-(isobutyryl)-2′-O-methyl-guanosine-3′-O-(2-cyano-ethyl-N,N-diisopropylamino)phosphoramidite,and5′-O-dimethoxy-trityl-2′-O-methyl-uridine-3′-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite.The 2′-Deoxy-2′-fluoro-phosphor-amidites carried the same protectinggroups as the 2′-O-methyl RNA amidites. The following UNAphosphoramidites were used:5′-(4,4′-Dimethoxytrityl)-N-benzoyl-2′,3′-seco-adenosine,2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphor-amidite,5′-(4,4′-Dimethoxytrityl)-N-acetyl-2′,3′-seco-cytosine,2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diiso-propyl)]-phosphoramidite,5′-(4,4′-Dimethoxytrityl)-N-isobutyryl-2′,3′-seco-guanosine,2′-benzyl-3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, and5′-(4,4′-Dimethoxy-trityl)-2′,3′-seco-uridine,2′-benzoyl-3′-[(2-cyanoethyl)-(N,N-diiso-propyl)]-phosphoramidite. Allamidites were dissolved in anhydrous acetonitrile (50 mM) and molecularsieves (3A) were added. In order to introduce the TEG-Cholesterol at the5′-end of the oligomers, the1-Dimethoxytrityloxy-3-O—(N-cholesteryl-3-aminopropyl)-triethyleneglycol-glyceryl-2-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramiditefrom Glen Research (Sterling, Va., USA) was employed. The5′-modifications were introduced without any modification of thesynthesis cycle. 5-Benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile)was used as activator solution. Coupling times were 10 min (RNA), 180sec (Cholesterol), 90 sec (2′OMe and UNA), and 60 sec (2′F and DNA). Inorder to introduce phosphorothioate linkages, a 100 mM solution of3-phenyl 1,2,4-dithiazoline-5-one (POS, obtained from PolyOrg, Inc.,Leominster, Mass., USA) in anhydrous Acetonitrile was employed. SeeTables 1, 2A, and 2B for specific sequences.

B. Cleavage and Deprotection of Support Bound Oligomer.

After finalization of the solid phase synthesis, the dried solid supportwas treated with a 1:1 volume solution of 40 wt. % methylamine in waterand 28% ammonium hydroxide solution (Aldrich) for two hours at 30° C.The solution was evaporated and the solid residue was reconstituted inwater (see below).

C. Purification.

Crude Cholesterol containing oligomers were purified by reverse phaseHPLC using a Waters XBridge BEH300 C4 5 u Prep column and a ShimadzuLC-8 system. Buffer A was 100 mM TEAA, pH 7.5 and contained 5%Acetonitrile and buffer B was 100 mM TEAA and contained 95%Acetonitrile. UV traces at 260 nm were recorded. Appropriate fractionswere then run on size exclusion HPLC using a GE Healthcare XK 16/40column packed with Sephadex G-25 medium with a running buffer of 100 mMammonium bicarbonate, pH 6.7 and 20% Acetonitrile. Other crude oligomerswere purified by anionic exchange HPLC using a TKSgel SuperQ-5PW 13 ucolumn and Shimadzu LC-8 system. Buffer A was 20 mM Tris, 5 mM EDTA, pH9.0 and contained 20% Acetonitrile and buffer B was the same as buffer Awith the addition of 1.5 M sodium chloride. UV traces at 260 nm wererecorded. Appropriate fractions were pooled then run on size exclusionHPLC as described for cholesterol containing oligomers.

D. Annealing.

Complementary strands were mixed by combining equimolar solutions (senseand antisense) in 0.2×PBS (Phosphate-Buffered Saline, 1×, Corning,Cellgro) to form the RNAi agents. This solution was placed into athermomixer at 70° C., heated to 95° C., held at 95° C. for 5 min, andcooled to room temperature slowly. Some RNAi agents were lyophilized andstored at −15 to −25° C. Duplex concentration was determined bymeasuring the solution absorbance on a UV-Vis spectrometer in 0.2×PBS.The solution absorbance at 260 nm was then multiplied by a conversionfactor and the dilution factor to determine the duplex concentration.Unless otherwise stated, all conversion factor was 0.037 mg/(mL·cm). Forsome experiments, a conversion factor was calculated from anexperimentally determined extinction coefficient.

Example 2. Primary In Vitro Analysis of LPA RNAi Agents

Candidate sequences identified as human and non-human primatecross-reactive by in silico analysis were screened. 108 insilico-identified potential LPA RNAi agents were synthesized andscreened for efficacy in vitro in three groups. For screening purposes,the human LPA cDNA sequence (accession # NM_005577.1) was sub-clonedfrom a commercially available mammalian expression vector (Origene,Rockville, Md.) into a commercially-available, reporter-based screeningplasmid, psiCHECK2 (Promega, Madison, Wis.) which generated a Renillaluciferase/LPA fusion mRNA. For LPA RNAi agent efficacy in the humanbackground, Hep3B cells, a human hepatocellular carcinoma line, wereplated at ˜10,000 cells per well in 96-well format. Each of the 108 LPARNAi agents was co-transfected at two or three concentrations (1 nM and0.1 nM, or 0.02, 0.2 and 2 nM) with 50-100 ng LPA-psiCHECK2 plasmid DNAper well and 0.2 μL LipoFectamine 2000 per well. Gene knockdown wasdetermined by measuring Renilla luciferase levels normalized to thelevels of constitutively-expressed firefly luciferase, also present onthe psiCHECK2 plasmid, using the Dual Luciferase Reporter Assay(Promega, Madison, Wis.) (Tables 5A and 5B).

TABLE 5A In vitro analyses of LPA RNAi agents, inhibition of LPAexpression. Relative R_(luc)-LPA expression Duplex 1 nM 0.1 nM ID#Average SD Average SD AD00571 1.012 0.146 1.107 0.174 AD00572 0.7760.062 1.075 0.089 AD00573 0.708 0.054 0.708 0.134 AD00574 0.441 0.0280.525 0.056 AD00575 0.242 0.038 0.365 0.035 AD00576 0.166 0.047 0.3410.073 AD00577 0.702 0.115 0.934 0.036 AD00578 0.272 0.008 0.599 0.200AD00579 0.290 0.031 0.447 0.066 AD00580 0.825 0.145 0.991 0.123 AD005810.654 0.095 0.986 0.127 AD00582 0.610 0.178 0.791 0.244 AD00583 0.8240.208 0.845 0.240 AD00584 0.800 0.150 0.683 0.077 AD00585 0.387 0.0590.488 0.151 AD00586 0.754 0.116 0.927 0.103 AD00587 0.921 0.074 0.9230.052 AD00588 0.763 0.203 0.954 0.169 AD00589 0.838 0.115 1.026 0.216AD00590 0.959 0.091 0.991 0.285 AD00591 0.970 0.172 0.984 0.244 AD005920.600 0.060 0.886 0.069 AD00593 0.555 0.097 0.883 0.130 AD00594 0.6450.056 0.567 0.008 AD00595 0.812 0.132 1.076 0.285 AD00596 0.658 0.1160.787 0.153 AD00597 0.999 0.120 1.083 0.143 AD00598 0.501 0.067 0.6310.036 AD00599 0.890 0.098 0.871 0.143 AD00600 0.393 0.018 0.729 0.172AD00601 0.896 0.180 1.142 0.140 AD00602 0.653 0.134 0.955 0.062 AD006030.730 0.118 0.799 0.187 AD00604 0.892 0.058 0.956 0.107 AD00605 1.0060.193 1.006 0.146 AD00606 0.509 0.039 0.570 0.054 AD00607 0.816 0.0910.906 0.068 AD00608 0.883 0.111 1.158 0.054 AD00609 0.515 0.079 0.6910.137 AD00610 0.628 0.057 0.748 0.090 AD00611 1.320 0.066 1.116 0.046AD00612 1.103 0.193 1.100 0.052 AD00613 0.910 0.094 0.878 0.040 AD006141.101 0.111 1.097 0.043 AD00615 1.051 0.140 0.898 0.161 AD00616 0.8980.101 1.029 0.042 AD00617 0.715 0.023 0.802 0.150 AD00618 0.434 0.0730.441 0.199 AD00619 0.758 0.003 0.820 0.165 AD00620 0.984 0.124 0.9260.080 AD00621 0.308 0.033 0.267 0.044 AD00622 0.493 0.072 0.790 0.009AD00623 0.641 0.081 0.599 0.014 AD00624 0.795 0.019 0.985 0.123 AD006250.768 0.121 0.944 0.117 AD00626 0.981 0.081 1.036 0.036 AD00627 0.9430.163 0.936 0.038 AD00628 0.765 0.069 0.995 0.090 AD00629 1.001 0.1841.199 0.064 AD00630 0.963 0.149 1.154 0.141 AD00631 0.979 0.084 1.0380.088 AD00632 0.781 0.048 0.858 0.101 AD00633 0.817 0.072 1.027 0.143AD00634 0.807 0.087 0.978 0.256 AD00635 0.496 0.073 0.377 0.023 AD006360.615 0.102 0.748 0.072 AD00637 0.792 0.056 1.070 0.048

TABLE 5B In vitro analyses of LPA RNAi agents, inhibition of LPAexpression. Relative R_(luc)-LPA expression Duplex 2 nM 0.2 nM 0.02 nMID# Average SD Average SD Average SD AD01068 0.780 0.110 0.792 0.3260.861 0.138 AD01069 0.483 0.345 1.062 0.181 0.869 0.112 AD01070 0.7470.441 1.010 0.015 1.015 0.319 AD01071 1.014 0.254 0.850 0.251 0.8570.284 AD01072 0.919 0.107 1.137 0.345 0.727 0.124 AD01073 0.539 0.2241.066 0.195 1.180 0.356 AD01074 0.713 0.545 0.953 0.419 0.841 0.077AD01075 0.703 0.379 0.913 0.204 0.965 0.216 AD01076 1.145 0.485 1.0270.287 0.647 0.154 AD01077 0.672 0.074 1.166 0.384 0.703 0.106 AD010780.575 0.192 0.847 0.237 0.908 0.071 AD01079 0.863 0.673 1.093 0.1871.004 0.086 AD01328 0.623 0.089 1.205 0.367 1.238 0.089 AD01329 0.4670.068 1.161 0.159 1.115 0.102 AD01330 1.158 0.124 0.920 0.143 1.1560.107 AD01331 1.476 0.225 1.092 0.269 1.304 0.320 AD01332 1.145 0.1091.100 0.454 0.941 0.510 AD01333 0.829 0.011 1.382 0.252 1.338 0.303AD01334 0.653 0.122 1.323 0.183 1.095 0.109 AD01335 0.858 0.089 1.6320.318 1.201 0.159 AD01336 1.019 0.081 1.724 0.353 1.008 0.072 AD013370.834 0.143 1.494 0.657 1.130 0.309 AD01338 1.276 0.340 0.719 0.1180.896 0.118 AD01339 1.240 0.298 1.114 0.287 0.960 0.104 AD01340 1.0550.423 1.272 0.136 1.338 0.299 AD01341 1.206 0.438 1.510 0.315 1.0460.143 AD01342 1.243 0.324 1.137 0.298 1.159 0.047 AD01343 1.113 0.1401.045 0.151 1.108 0.094 AD01344 0.931 0.182 1.317 0.244 1.328 0.037AD01345 0.795 0.233 0.799 0.032 1.418 0.184 AD01346 1.095 0.224 1.0450.073 1.465 0.109 AD01347 1.122 0.021 1.209 0.161 1.153 0.159 AD013481.022 0.068 1.228 0.244 1.097 0.049 AD01349 0.934 0.151 1.217 0.0801.068 0.149 AD01350 0.871 0.295 1.318 0.225 0.942 0.395 AD01351 1.4140.065 1.121 0.180 1.029 0.049 AD01352 0.868 0.088 1.024 0.385 1.0490.176 AD01353 1.150 0.478 1.164 0.276 0.898 0.175 AD01354 0.999 0.1191.378 0.292 1.507 0.289 AD01355 0.943 0.092 1.066 0.268 1.411 0.113AD01356 1.116 0.351 1.072 0.196 1.000 0.145

TABLE 5C In vitro analyses of 10 mM LPA RNAi agents, inhibition of LPAexpression. Duplex No. LPA levels AD01803 0.77 ± 0.06 AD01805 0.77 ±0.02 AD01806 1.01 ± 0.02 AD01807 0.97 ± 0.09 AD01808 0.78 ± 0.12 AD018091.06 ± 0.13 AD01810 1.06 ± 0.05 AD01811 0.86 ± 0.05 AD01812 1.08 ± 0.04AD01813 0.99 ± 0.13 AD01814 0.57 ± 0.05 AD01815 0.65 ± 0.00 AD01816 0.84± 0.08 AD01817 0.75 ± 0.10 AD01818 0.94 ± 0.07 AD01819 1.21 ± 0.08AD01820 1.22 ± 0.12 AD01821 1.16 ± 0.01 AD01822 1.22 ± 0.04 AD01823 0.91± 0.05 AD01824 1.22 ± 0.13 AD01825 1.25 ± 0.05 AD01826 1.18 ± 0.15AD01827 1.23 ± 0.07 AD01828 1.02 ± 0.09 AD01829 1.05 ± 0.07 AD01830 1.00± 0.35 AD01831 1.02 ± 0.07 AD01832 1.04 ± 0.06 AD01896 0.71 ± 0.14AD01897 0.87 ± 0.10 AD01898 1.16 ± 0.03 AD01899 0.79 ± 0.11 AD01900 0.82± 0.06 AD01901 0.54 ± 0.04 AD01902 0.62 ± 0.00 AD01903 0.66 ± 0.08AD01912 0.59 ± 0.01 AD01913 0.60 ± 0.04 AD01914 0.50 ± 0.03 AD01915 0.58± 0.08 AD01916 0.49 ± 0.04 AD01917 0.53 ± 0.04 AD01918 0.47 ± 0.04AD01919 0.60 ± 0.02 AD01920 0.60 ± 0.03 AD01921 0.59 ± 0.06 AD01922 0.50± 0.04 AD01923 0.59 ± 0.04 AD01924 0.50 ± 0.02 AD01925 0.54 ± 0.05AD01926 0.52 ± 0.05 AD01927 0.57 ± 0.04 AD01928 0.50 ± 0.06 AD01929 0.55± 0.04 AD01930 0.54 ± 0.06 AD01931 0.54 ± 0.07 AD01932 0.51 ± 0.01AD01933 0.56 ± 0.06 AD01934 0.52 ± 0.08 AD01935 0.58 ± 0.03 AD01936 0.53± 0.02 AD01937 0.57 ± 0.04 AD01938 0.58 ± 0.03 AD01939 0.65 ± 0.05AD01940 0.49 ± 0.03 AD01941 0.57 ± 0.02

TABLE 5D In vitro analyses of 1 mM LPA RNAi agents, inhibition of LPAexpression. Duplex No. LPA levels AD01760 0.10 ± 0.01 AD01722 0.14 ±0.01 AD01757 0.15 ± 0.00 AD01719 0.15 ± 0.00 AD01738 0.18 ± 0.01 AD017550.19 ± 0.01 AD01741 0.20 ± 0.00 AD01759 0.23 ± 0.02 AD01747 0.23 ± 0.03AD01752 0.24 ± 0.03 AD01736 0.24 ± 0.02 AD02311 0.25 ± 0.05 AD02201 0.25± 0.03 AD01750 0.25 ± 0.00 AD01756 0.25 ± 0.01 AD02291 0.25 ± 0.03AD02292 0.26 ± 0.01 AD02266 0.26 ± 0.02 AD01763 0.26 ± 0.01 AD02259 0.26± 0.03 AD02327 0.26 ± 0.02 AD02274 0.27 ± 0.03 AD02297 0.27 ± 0.02AD02147 0.27 ± 0.03 AD02365 0.27 ± 0.04 AD02260 0.27 ± 0.03 AD02368 0.27± 0.01 AD02265 0.28 ± 0.03 AD02293 0.28 ± 0.04 AD02350 0.28 ± 0.02AD02202 0.28 ± 0.03 AD02203 0.28 ± 0.03 AD02258 0.28 ± 0.05 AD02295 0.28± 0.03 AD02363 0.28 ± 0.04 AD02273 0.28 ± 0.02 AD02386 0.28 ± 0.02AD02309 0.28 ± 0.03 AD02382 0.29 ± 0.01 AD02256 0.29 ± 0.02 AD02367 0.29± 0.03 AD02275 0.29 ± 0.04 AD02206 0.29 ± 0.01 AD02332 0.29 ± 0.02AD01717 0.29 ± 0.03 AD02296 0.29 ± 0.01 AD02264 0.29 ± 0.03 AD02278 0.29± 0.03 AD02385 0.29 ± 0.00 AD02205 0.29 ± 0.04 AD02149 0.29 ± 0.02AD02239 0.30 ± 0.05 AD01748 0.30 ± 0.02 AD02404 0.30 ± 0.01 AD01721 0.30± 0.03 AD02277 0.30 ± 0.05 AD02152 0.30 ± 0.01 AD02237 0.30 ± 0.02AD02098 0.30 ± 0.03 AD02381 0.30 ± 0.02 AD02315 0.30 ± 0.02 AD02366 0.30± 0.01 AD02242 0.31 ± 0.03 AD02294 0.31 ± 0.02 AD02346 0.31 ± 0.04AD02329 0.31 ± 0.02 AD02348 0.31 ± 0.01 AD01714 0.31 ± 0.05 AD01724 0.31± 0.01 AD02170 0.31 ± 0.02 AD02352 0.31 ± 0.02 AD02093 0.31 ± 0.01AD02383 0.31 ± 0.02 AD02284 0.31 ± 0.04 AD02219 0.31 ± 0.04 AD02279 0.31± 0.03 AD02299 0.31 ± 0.05 AD01740 0.31 ± 0.02 AD02417 0.32 ± 0.01AD02364 0.32 ± 0.02 AD02262 0.32 ± 0.03 AD02369 0.32 ± 0.01 AD01731 0.32± 0.02 AD02349 0.32 ± 0.01 AD02095 0.32 ± 0.02 AD02281 0.32 ± 0.01AD02224 0.32 ± 0.06 AD02148 0.32 ± 0.04 AD01718 0.33 ± 0.01 AD02333 0.33± 0.01 AD02403 0.33 ± 0.01 AD02317 0.33 ± 0.03 AD02399 0.33 ± 0.02AD02222 0.33 ± 0.01 AD02310 0.33 ± 0.02 AD01733 0.33 ± 0.01 AD02131 0.33± 0.01 AD02353 0.33 ± 0.03 AD02263 0.33 ± 0.03 AD02204 0.33 ± 0.01AD02080 0.33 ± 0.00 AD02298 0.33 ± 0.03 AD01737 0.33 ± 0.01 AD02220 0.33± 0.04 AD02302 0.33 ± 0.00 AD02097 0.33 ± 0.00 AD02328 0.33 ± 0.02AD02221 0.33 ± 0.01 AD02421 0.33 ± 0.02 AD02420 0.33 ± 0.03 AD02347 0.33± 0.04 AD02134 0.34 ± 0.01 AD02078 0.34 ± 0.03 AD02151 0.34 ± 0.02AD02238 0.34 ± 0.03 AD02168 0.34 ± 0.00 AD02096 0.34 ± 0.03 AD01758 0.34± 0.05 AD02077 0.34 ± 0.02 AD02345 0.34 ± 0.02 AD02384 0.34 ± 0.02AD02094 0.34 ± 0.01 AD02419 0.34 ± 0.04 AD02401 0.34 ± 0.02 AD02402 0.34± 0.03 AD01712 0.34 ± 0.04 AD02276 0.34 ± 0.01 AD02150 0.34 ± 0.02AD02166 0.34 ± 0.03 AD02351 0.34 ± 0.02 AD02241 0.35 ± 0.04 AD02282 0.35± 0.01 AD02130 0.35 ± 0.04 AD01751 0.35 ± 0.03 AD02356 0.35 ± 0.03AD02405 0.35 ± 0.04 AD02129 0.35 ± 0.01 AD02355 0.35 ± 0.01 AD02423 0.35± 0.06 AD02316 0.35 ± 0.02 AD02331 0.35 ± 0.02 AD02335 0.35 ± 0.01AD02187 0.35 ± 0.03 AD02314 0.36 ± 0.04 AD02300 0.36 ± 0.03 AD02387 0.36± 0.06 AD02337 0.36 ± 0.04 AD01729 0.36 ± 0.01 AD02283 0.36 ± 0.02AD02185 0.36 ± 0.01 AD02167 0.36 ± 0.01 AD02076 0.36 ± 0.04 AD02418 0.36± 0.01 AD02422 0.36 ± 0.03 AD02111 0.36 ± 0.02 AD02079 0.37 ± 0.02AD01754 0.37 ± 0.04 AD02334 0.37 ± 0.02 AD02280 0.37 ± 0.05 AD02113 0.37± 0.03 AD02389 0.37 ± 0.03 AD02223 0.37 ± 0.04 AD02184 0.37 ± 0.02AD02153 0.37 ± 0.02 AD02165 0.37 ± 0.02 AD02207 0.37 ± 0.01 AD02330 0.37± 0.01 AD02243 0.37 ± 0.02 AD02255 0.38 ± 0.02 AD02257 0.38 ± 0.00AD02169 0.38 ± 0.02 AD02081 0.38 ± 0.00 AD02186 0.38 ± 0.02 AD01744 0.38± 0.03 AD02075 0.38 ± 0.01 AD02135 0.38 ± 0.03 AD02114 0.38 ± 0.04AD02188 0.38 ± 0.04 AD02318 0.38 ± 0.02 AD02388 0.38 ± 0.02 AD02115 0.38± 0.04 AD02133 0.38 ± 0.00 AD02183 0.38 ± 0.04 AD02116 0.38 ± 0.02AD02132 0.39 ± 0.03 AD02400 0.39 ± 0.02 AD02338 0.39 ± 0.04 AD02112 0.39± 0.01 AD02354 0.39 ± 0.05 AD01749 0.40 ± 0.06 AD02312 0.40 ± 0.02AD02240 0.40 ± 0.00 AD02313 0.40 ± 0.03 AD01710 0.40 ± 0.05 AD02301 0.40± 0.05 AD02425 0.40 ± 0.04 AD02099 0.41 ± 0.04 AD01723 0.41 ± 0.04AD02391 0.41 ± 0.03 AD02392 0.41 ± 0.05 AD02083 0.41 ± 0.01 AD02155 0.41± 0.02 AD02082 0.41 ± 0.01 AD02336 0.41 ± 0.01 AD02101 0.41 ± 0.02AD01728 0.42 ± 0.01 AD02424 0.42 ± 0.04 AD02175 0.42 ± 0.02 AD02225 0.42± 0.05 AD02086 0.43 ± 0.02 AD01725 0.43 ± 0.06 AD02374 0.43 ± 0.03AD02390 0.43 ± 0.04 AD02227 0.43 ± 0.02 AD02137 0.43 ± 0.06 AD02085 0.43± 0.01 AD02407 0.43 ± 0.03 AD02100 0.44 ± 0.04 AD02406 0.44 ± 0.04AD02136 0.44 ± 0.02 AD02209 0.44 ± 0.03 AD02154 0.44 ± 0.02 AD02171 0.44± 0.01 AD02261 0.45 ± 0.02 AD02271 0.45 ± 0.00 AD02371 0.45 ± 0.03AD02173 0.45 ± 0.07 AD02319 0.45 ± 0.01 AD02176 0.46 ± 0.01 AD02428 0.46± 0.02 AD02410 0.46 ± 0.01 AD01746 0.46 ± 0.05 AD01732 0.46 ± 0.02AD02157 0.47 ± 0.02 AD02372 0.47 ± 0.03 AD02427 0.47 ± 0.02 AD02370 0.47± 0.01 AD02172 0.47 ± 0.04 AD02158 0.47 ± 0.02 AD02270 0.48 ± 0.04AD02426 0.48 ± 0.04 AD02361 0.48 ± 0.04 AD02245 0.48 ± 0.02 AD02373 0.48± 0.01 AD02084 0.48 ± 0.05 AD02194 0.48 ± 0.03 AD01753 0.48 ± 0.06AD02320 0.48 ± 0.03 AD02268 0.48 ± 0.05 AD02226 0.49 ± 0.01 AD02156 0.49± 0.01 AD02409 0.49 ± 0.03 AD02244 0.49 ± 0.02 AD02189 0.49 ± 0.06AD01764 0.50 ± 0.02 AD02174 0.50 ± 0.04 AD02117 0.50 ± 0.01 AD02208 0.50± 0.05 AD02104 0.51 ± 0.03 AD02408 0.51 ± 0.06 AD02272 0.51 ± 0.04AD02122 0.51 ± 0.06 AD02140 0.51 ± 0.04 AD02362 0.51 ± 0.04 AD01739 0.52± 0.04 AD02121 0.52 ± 0.06 AD02138 0.52 ± 0.04 AD02358 0.52 ± 0.02AD01734 0.53 ± 0.06 AD01713 0.53 ± 0.04 AD02285 0.53 ± 0.03 AD02102 0.53± 0.07 AD02303 0.53 ± 0.03 AD02212 0.53 ± 0.01 AD02139 0.53 ± 0.03AD02230 0.54 ± 0.08 AD02103 0.54 ± 0.04 AD02191 0.54 ± 0.03 AD02429 0.54± 0.02 AD01716 0.54 ± 0.09 AD02360 0.54 ± 0.02 AD01762 0.54 ± 0.01AD01735 0.55 ± 0.07 AD02248 0.55 ± 0.05 AD02193 0.55 ± 0.01 AD02119 0.55± 0.01 AD02287 0.55 ± 0.02 AD02357 0.56 ± 0.01 AD01708 0.57 ± 0.06AD02247 0.57 ± 0.06 AD02430 0.58 ± 0.07 AD02339 0.58 ± 0.03 AD02321 0.59± 0.03 AD02269 0.59 ± 0.02 AD02210 0.59 ± 0.04 AD02211 0.60 ± 0.02AD02091 0.60 ± 0.03 AD02120 0.60 ± 0.07 AD02229 0.60 ± 0.03 AD01727 0.60± 0.02 AD01730 0.60 ± 0.02 AD02190 0.60 ± 0.07 AD02411 0.60 ± 0.06AD02322 0.61 ± 0.03 AD02433 0.61 ± 0.02 AD01761 0.62 ± 0.05 AD01720 0.62± 0.02 AD02228 0.62 ± 0.06 AD02393 0.62 ± 0.03 AD02359 0.62 ± 0.03AD02323 0.62 ± 0.05 AD02118 0.63 ± 0.05 AD02286 0.63 ± 0.04 AD02087 0.63± 0.04 AD01715 0.63 ± 0.06 AD02192 0.63 ± 0.02 AD02431 0.64 ± 0.06AD02340 0.64 ± 0.03 AD02432 0.64 ± 0.02 AD02089 0.65 ± 0.07 AD02267 0.65± 0.11 AD02246 0.65 ± 0.07 AD02325 0.65 ± 0.03 AD02343 0.66 ± 0.05AD02375 0.66 ± 0.04 AD02288 0.66 ± 0.06 AD02088 0.66 ± 0.01 AD02413 0.66± 0.03 AD02377 0.67 ± 0.05 AD02528 0.67 ± 0.04 AD02434 0.67 ± 0.05AD02304 0.67 ± 0.02 AD02090 0.68 ± 0.04 AD02161 0.68 ± 0.04 AD02324 0.68± 0.02 AD02177 0.69 ± 0.07 AD02179 0.69 ± 0.07 AD02527 0.69 ± 0.03AD02305 0.69 ± 0.06 AD02092 0.70 ± 0.02 AD02535 0.70 ± 0.10 AD02376 0.71± 0.04 AD01743 0.71 ± 0.02 AD02289 0.71 ± 0.04 AD02530 0.71 ± 0.06AD01709 0.71 ± 0.12 AD02249 0.71 ± 0.06 AD02534 0.71 ± 0.03 AD02213 0.71± 0.02 AD02529 0.71 ± 0.03 AD01711 0.71 ± 0.06 AD02341 0.72 ± 0.06AD02233 0.72 ± 0.06 AD02342 0.73 ± 0.04 AD02395 0.73 ± 0.06 AD02306 0.73± 0.09 AD02344 0.73 ± 0.04 AD02145 0.74 ± 0.09 AD02326 0.74 ± 0.06AD02414 0.74 ± 0.04 AD02379 0.74 ± 0.06 AD02532 0.75 ± 0.04 AD02178 0.75± 0.11 AD02195 0.75 ± 0.05 AD02123 0.76 ± 0.07 AD02164 0.77 ± 0.09AD01726 0.77 ± 0.01 AD02231 0.77 ± 0.05 AD02180 0.77 ± 0.04 AD02412 0.77± 0.05 AD02251 0.77 ± 0.02 AD02396 0.78 ± 0.13 AD02160 0.78 ± 0.04AD02533 0.78 ± 0.05 AD02290 0.78 ± 0.03 AD02378 0.78 ± 0.07 AD02394 0.79± 0.04 AD02415 0.79 ± 0.05 AD02181 0.79 ± 0.08 AD02492 0.79 ± 0.06AD02397 0.79 ± 0.05 AD02398 0.79 ± 0.09 AD02416 0.79 ± 0.04 AD02144 0.79± 0.09 AD02531 0.79 ± 0.06 AD02489 0.80 ± 0.04 AD02307 0.80 ± 0.10AD02308 0.80 ± 0.11 AD02182 0.80 ± 0.08 AD02198 0.80 ± 0.11 AD02199 0.80± 0.10 AD02200 0.80 ± 0.06 AD02125 0.81 ± 0.06 AD02141 0.81 ± 0.01AD02516 0.81 ± 0.06 AD02127 0.81 ± 0.06 AD02380 0.81 ± 0.03 AD02124 0.81± 0.05 AD02197 0.81 ± 0.02 AD02159 0.81 ± 0.09 AD02485 0.82 ± 0.04AD02142 0.82 ± 0.08 AD02126 0.82 ± 0.08 AD02254 0.82 ± 0.10 AD02232 0.82± 0.04 AD02146 0.82 ± 0.04 AD02490 0.82 ± 0.03 AD01745 0.82 ± 0.09AD02162 0.83 ± 0.04 AD02471 0.83 ± 0.11 AD02487 0.83 ± 0.09 AD02523 0.83± 0.10 AD02483 0.83 ± 0.03 AD02128 0.84 ± 0.09 AD02143 0.84 ± 0.05AD02214 0.84 ± 0.13 AD02217 0.84 ± 0.07 AD02250 0.84 ± 0.08 AD02163 0.85± 0.04 AD02525 0.85 ± 0.06 AD02481 0.85 ± 0.03 AD02235 0.85 ± 0.03AD02539 0.86 ± 0.05 AD02470 0.86 ± 0.07 AD02469 0.86 ± 0.04 AD02480 0.86± 0.07 AD02488 0.87 ± 0.05 AD02511 0.87 ± 0.05 AD02482 0.87 ± 0.04AD02519 0.87 ± 0.08 AD02491 0.88 ± 0.05 AD02216 0.88 ± 0.00 AD02215 0.88± 0.03 AD02468 0.88 ± 0.06 AD02526 0.88 ± 0.06 AD02234 0.88 ± 0.14AD02518 0.89 ± 0.05 AD02218 0.89 ± 0.04 AD02515 0.89 ± 0.03 AD02536 0.89± 0.11 AD02537 0.89 ± 0.04 AD02465 0.89 ± 0.07 AD02196 0.90 ± 0.03AD02253 0.90 ± 0.05 AD02484 0.90 ± 0.09 AD02467 0.91 ± 0.00 AD02538 0.91± 0.10 AD02478 0.91 ± 0.01 AD02479 0.92 ± 0.05 AD02540 0.92 ± 0.08AD02524 0.92 ± 0.03 AD02466 0.92 ± 0.05 AD02520 0.92 ± 0.06 AD02498 0.92± 0.06 AD02472 0.92 ± 0.05 AD02106 0.93 ± 0.08 AD02486 0.93 ± 0.02AD02236 0.93 ± 0.04 AD02543 0.93 ± 0.12 AD02517 0.94 ± 0.05 AD02505 0.94± 0.10 AD02464 0.94 ± 0.06 AD02499 0.94 ± 0.16 AD02500 0.94 ± 0.05AD02544 0.95 ± 0.07 AD02541 0.95 ± 0.15 AD02509 0.95 ± 0.09 AD02508 0.95± 0.10 AD02510 0.95 ± 0.03 AD02521 0.96 ± 0.16 AD02507 0.96 ± 0.03AD02105 0.96 ± 0.09 AD02495 0.96 ± 0.05 AD02504 0.97 ± 0.04 AD02493 0.97± 0.06 AD02542 0.97 ± 0.06 AD02503 0.98 ± 0.05 AD02107 0.98 ± 0.05AD02477 0.98 ± 0.06 AD02501 0.98 ± 0.07 AD02497 0.98 ± 0.05 AD02494 0.98± 0.13 AD02475 1.00 ± 0.07 AD02514 1.00 ± 0.00 AD02474 1.00 ± 0.03AD02502 1.01 ± 0.01 AD02522 1.01 ± 0.04 AD02476 1.01 ± 0.09 AD02513 1.02± 0.03 AD02109 1.02 ± 0.06 AD02252 1.02 ± 0.08 AD02496 1.04 ± 0.05AD02473 1.05 ± 0.04 AD02506 1.05 ± 0.05 AD01742 1.07 ± 0.24 AD02110 1.08± 0.07 AD02512 1.09 ± 0.17 AD02108 1.11 ± 0.04

Example 3. LPA RNAi Agent EC₅₀ Determination

Ten-point EC₅₀ curves were generated using the same cells andtransfection conditions, with LPA RNAi agent concentrations ranging from150 fM-3 nM. EC₅₀ were determined using GraphPad Prism software (Table6).

TABLE 6 EC₅₀ values (nM) determined in vitro for the indicated LPA RNAiagents. Duplex ID# EC₅₀ (nM) AD00575 0.073 AD00576 0.038 AD00578 0.112AD00579 0.083 AD00621 0.100 AD00635 0.577 AD01070 0.6388 AD01072 0.1068AD01073 0.1154 AD01074 0.2903

Example 4. In Vitro Analysis of Structure-Activity Relationship (SAR)Designed LPA RNAi Agents

LPA RNAi agent SAR sets (364 sequences based on AD01532 and 351sequences based on AD01533) were synthesized and screened for efficacyin vitro. For screening purposes, 2756 bp of the human LPA cDNA sequencefrom KIV-3 to KIV-9 (accession # NM_005577.1) was synthesized and cloned(GeneWiz, South Plainfield, N.J.) into a commercially-available,reporter-based screening plasmid, psiCHECK2 (Promega, Madison, Wis.)which generated a Renilla luciferase/LPA fusion mRNA. For LPA RNAi agentefficacy in the human background. HuH7 cells, a human hepatocellularcarcinoma line, were plated at ˜7500 cells per well in 96-well format.Each of the LPA RNAi agents was co-transfected at two concentrations (1nM and 0.1 nM, or 10 nM and 1 nM) with 25 ng LPA-psiCHECK2 plasmid DNAper well and 0.2 μL LipoFectamine 2000 per well. Gene knockdown wasdetermined by measuring Renilla luciferase levels normalized to thelevels of constitutively-expressed firefly luciferase, also present onthe psiCHECK2 plasmid, using the Dual Luciferase Reporter Assay(Promega, Madison, Wis.) (Tables 7A and 7B).

TABLE 7A Efficacy screen results of LPA RNAi agents in vitro, asdetermined by dual-luciferase reporter assay. Relative R_(luc)-LPADuplex expression ID No. 1 nM 0.1 nM SD0001 0.570 0.907 SD0002 0.8731.061 SD0003 0.955 1.020 SD0004 0.845 1.007 SD0005 0.603 0.891 SD00060.551 0.780 SD0007 0.510 0.797 SD0008 0.544 0.892 SD0009 0.564 0.878SD0010 0.542 1.051 SD0011 0.513 0.873 SD0012 0.533 0.963 SD0013 0.5410.979 SD0014 0.551 0.987 SD0015 0.488 0.951 SD0016 0.588 0.868 SD00171.023 1.005 SD0018 0.866 0.965 SD0019 0.792 1.005 SD0020 0.633 0.860SD0021 0.572 0.797 SD0022 0.610 0.874 SD0023 0.550 0.836 SD0024 0.5970.859 SD0025 0.587 0.899 SD0026 0.570 0.898 SD0027 0.580 0.825 SD00280.612 0.885 SD0029 0.528 0.866 SD0030 0.657 0.825 SD0031 0.560 0.914SD0032 0.664 0.976 SD0033 0.787 1.035 SD0034 0.739 1.002 SD0035 0.6580.949 SD0036 0.554 0.896 SD0037 0.557 0.873 SD0038 0.528 0.854 SD00390.511 0.847 SD0040 0.554 0.976 SD0041 0.559 0.823 SD0042 0.496 0.825SD0043 0.563 0.851 SD0044 0.476 0.861 SD0045 0.542 0.841 SD0046 0.6510.980 SD0047 0.967 0.995 SD0048 0.694 0.936 SD0049 0.960 0.946 SD00500.692 0.971 SD0051 0.611 0.905 SD0052 0.657 0.849 SD0053 0.642 0.848SD0054 0.598 0.852 SD0055 0.494 0.828 SD0056 0.524 0.885 SD0057 0.5820.816 SD0058 0.597 0.866 SD0059 0.560 0.905 SD0060 0.594 0.849 SD00610.571 1.058 SD0062 0.871 1.157 SD0063 0.969 1.138 SD0064 0.555 1.019SD0065 0.671 0.953 SD0066 0.561 0.951 SD0067 0.612 0.904 SD0068 0.5730.938 SD0069 0.574 0.975 SD0070 0.606 1.030 SD0071 0.494 0.959 SD00720.557 0.892 SD0073 0.593 0.984 SD0074 0.544 0.894 SD0075 0.552 0.937SD0076 0.513 1.058 SD0077 0.930 1.071 SD0078 0.984 1.006 SD0079 0.8531.031 SD0080 0.577 0.942 SD0081 0.595 1.044 SD0082 0.652 0.962 SD00830.583 0.928 SD0084 0.540 1.049 SD0085 0.523 0.961 SD0086 0.536 0.956SD0087 0.586 0.987 SD0088 0.563 0.892 SD0089 0.555 0.947 SD0090 0.5990.928 SD0091 0.665 0.854 SD0092 1.002 0.917 SD0093 1.047 0.880 SD00940.867 0.911 SD0095 0.919 0.868 SD0096 0.666 0.887 SD0097 0.673 0.737SD0098 0.567 0.809 SD0099 0.604 0.909 SD0100 0.557 0.880 SD0101 0.5450.806 SD0102 0.728 0.900 SD0103 0.719 0.928 SD0104 0.766 0.955 SD01050.965 0.927 SD0106 1.161 1.006 SD0107 1.048 0.966 SD0108 1.066 0.985SD0109 1.111 0.917 SD0110 1.152 0.954 SD0111 1.045 0.944 SD0112 1.0891.019 SD0113 0.949 0.935 SD0114 0.875 1.033 SD0115 1.022 1.077 SD01160.947 1.028 SD0117 0.946 1.021 SD0118 0.879 0.977 SD0119 0.963 1.016SD0120 0.967 0.948 SD0121 0.651 0.897 SD0122 1.085 1.111 SD0123 1.1531.052 SD0124 0.955 0.936 SD0125 0.928 0.928 SD0126 1.033 0.933 SD01270.637 0.717 SD0128 0.630 0.653 SD0129 1.052 1.192 SD0130 1.025 1.107SD0131 1.280 1.059 SD0132 1.094 1.024 SD0133 1.113 1.031 SD0134 0.9280.991 SD0135 0.804 1.023 SD0136 1.028 1.104 SD0137 0.902 1.149 SD01380.942 1.015 SD0139 0.984 1.068 SD0140 0.953 1.091 SD0141 0.925 1.022SD0142 0.906 0.994 SD0143 0.898 0.990 SD0144 0.858 0.972 SD0145 0.9170.947 SD0146 0.850 0.906 SD0147 0.933 0.995 SD0148 0.856 0.994 SD01490.882 0.985 SD0150 0.810 1.002 SD0151 0.813 0.909 SD0152 0.963 1.031SD0153 1.058 0.936 SD0154 0.968 0.944 SD0155 0.969 0.940 SD0156 0.9330.807 SD0157 0.906 0.913 SD0158 0.926 0.964 SD0159 0.805 0.850 SD01600.895 0.965 SD0161 0.865 1.006 SD0162 0.935 1.029 SD0163 0.928 0.985SD0164 0.920 0.957 SD0165 1.039 1.110 SD0166 1.061 1.023 SD0167 1.0200.982 SD0168 1.053 0.989 SD0169 1.002 1.018 SD0170 1.078 0.982 SD01710.838 0.923 SD0172 1.025 0.934 SD0173 0.864 0.963 SD0174 1.020 1.043SD0175 1.128 1.046 SD0176 1.009 1.110 SD0177 0.735 0.975 SD0178 0.8241.074 SD0179 0.690 0.895 SD0180 0.572 0.914 SD0181 0.904 1.028 SD01821.176 1.093 SD0183 1.247 1.090 SD0184 1.097 0.974 SD0185 1.045 0.985SD0186 0.940 0.943 SD0187 0.883 0.994 SD0188 ND ND SD0189 0.872 0.977SD0190 0.861 1.166 SD0191 0.779 1.044 SD0192 0.796 1.116 SD0193 0.9751.112 SD0194 0.876 1.058 SD0195 0.747 0.970 SD0196 0.787 1.086 SD01971.276 1.127 SD0198 1.144 1.140 SD0199 1.136 1.101 SD0200 0.814 0.911SD0201 0.733 0.915 SD0202 0.576 0.933 SD0203 0.593 0.824 SD0204 0.8821.038 SD0205 0.681 1.012 SD0206 0.600 0.927 SD0207 0.738 0.974 SD02080.638 0.883 SD0209 0.641 0.878 SD0210 0.544 0.886 SD0211 0.702 0.920SD0212 0.704 0.854 SD0213 0.655 0.887 SD0214 0.629 0.860 SD0215 0.5980.850 SD0216 0.611 0.782 SD0217 0.710 0.806 SD0218 0.738 0.758 SD02190.664 0.809 SD0220 1.133 0.891 SD0221 0.940 0.914 SD0222 0.853 0.882SD0223 0.691 0.889 SD0224 0.997 1.033 SD0225 0.954 0.998 SD0226 1.2020.997 SD0227 0.948 1.017 SD0228 0.786 0.947 SD0229 0.620 0.830 SD02300.840 0.972 SD0231 0.904 0.890

TABLE 7B Efficacy screen results of LPA RNAi agents in vitro, asdetermined by dual-luciferase reporter assay. Relative R_(luc)-LPADuplex expression ID # 10 nM 1 nM SD0232 0.659 0.699 SD0233 0.942 1.252SD0234 0.967 1.358 SD0235 0.910 0.890 SD0236 0.742 0.822 SD0237 0.7580.831 SD0238 0.700 0.737 SD0239 0.645 0.765 SD0240 0.701 0.773 SD02410.770 0.821 SD0242 0.626 0.719 SD0243 0.759 0.848 SD0244 0.798 0.953SD0245 0.764 0.821 SD0246 0.812 0.690 SD0247 0.786 0.844 SD0248 1.0111.167 SD0249 1.118 1.189 SD0250 1.021 1.239 SD0251 1.041 1.151 SD02521.070 1.124 SD0253 1.044 1.131 SD0254 0.861 0.948 SD0255 0.751 0.829SD0256 0.931 1.037 SD0257 1.024 1.037 SD0258 0.935 1.030 SD0259 1.0891.081 SD0260 0.955 1.008 SD0261 0.923 0.980 SD0262 0.908 1.107 SD02631.060 1.449 SD0264 1.041 1.419 SD0265 1.065 1.373 SD0266 0.950 1.376SD0267 0.963 1.214 SD0268 1.023 1.299 SD0269 0.908 1.066 SD0270 0.9631.081 SD0271 1.088 1.189 SD0272 0.966 1.135 SD0273 0.953 1.192 SD02741.049 1.217 SD0275 1.006 1.206 SD0276 0.969 1.064 SD0277 0.686 0.796SD0278 0.985 1.305 SD0279 0.985 1.301 SD0280 0.978 1.237 SD0281 1.0381.230 SD0282 0.933 1.191 SD0283 0.930 1.152 SD0284 0.907 1.117 SD02850.625 0.870 SD0286 0.984 1.056 SD0287 0.906 0.965 SD0288 1.052 1.123SD0289 0.997 1.215 SD0290 0.892 1.197 SD0291 0.907 1.065 SD0292 0.6890.862 SD0293 0.955 1.190 SD0294 1.095 1.157 SD0295 0.851 1.004 SD02961.018 1.106 SD0297 0.737 0.760 SD0298 0.790 0.828 SD0299 0.721 0.713SD0300 0.796 0.869 SD0301 0.781 0.841 SD0302 0.621 0.720 SD0303 0.6840.852 SD0304 0.774 0.842 SD0305 0.778 0.799 SD0306 0.718 0.793 SD03070.982 0.883 SD0308 1.297 1.193 SD0309 1.123 1.208 SD0310 0.961 1.073SD0311 1.168 1.019 SD0312 0.923 0.824 SD0313 0.883 0.871 SD0314 0.6700.650 SD0315 0.988 0.958 SD0316 0.908 0.880 SD0317 0.754 0.850 SD03180.963 0.944 SD0319 0.945 0.862 SD0320 0.961 0.875 SD0321 0.841 0.797SD0322 0.546 0.521 SD0323 0.581 0.895 SD0324 0.692 0.900 SD0325 0.5060.796 SD0326 0.634 0.709 SD0327 0.522 0.592 SD0328 0.602 0.632 SD03290.504 0.615 SD0330 0.445 0.601 SD0331 0.457 0.579 SD0332 0.500 0.601SD0333 0.447 0.618 SD0334 0.490 0.528 SD0335 0.421 0.555 SD0336 0.4880.533 SD0337 1.714 0.978 SD0338 1.262 1.350 SD0339 1.259 1.357 SD03400.996 1.277 SD0341 1.190 1.183 SD0342 0.818 0.923 SD0343 0.803 0.855SD0344 0.708 0.883 SD0345 1.132 0.901 SD0346 0.847 0.890 SD0347 0.6590.780 SD0348 0.730 0.945 SD0349 0.825 0.886 SD0350 0.826 0.897 SD03510.730 0.842 SD0352 0.297 0.276 SD0353 0.773 0.746 SD0354 0.663 0.722SD0355 0.620 0.626 SD0356 0.546 0.599 SD0357 0.298 0.411 SD0358 0.3130.318 SD0359 0.273 0.282 SD0360 0.256 0.257 SD0361 0.269 0.276 SD03620.270 0.276 SD0363 0.350 0.272 SD0364 0.227 0.243 SD0365 0.228 0.233SD0366 0.264 0.241 SD0367 0.262 0.252 SD0368 0.571 0.597 SD0369 0.5390.531 SD0370 0.521 0.545 SD0371 0.302 0.319 SD0372 0.353 0.335 SD03730.279 0.255 SD0374 0.266 0.194 SD0375 0.246 0.238 SD0376 0.258 0.238SD0377 0.246 0.226 SD0378 0.237 0.226 SD0379 0.262 0.226 SD0380 0.2470.240 SD0381 0.639 0.657 SD0382 0.267 0.517 SD0383 0.473 0.547 SD03840.456 0.563 SD0385 0.264 0.393 SD0386 0.329 0.325 SD0387 0.186 0.231SD0388 0.217 0.248 SD0389 0.230 0.275 SD0390 0.210 0.270 SD0391 0.2470.224 SD0392 0.257 0.236 SD0393 0.252 0.253 SD0394 0.267 0.251 SD03950.594 0.675 SD0396 0.511 0.678 SD0397 0.457 0.618 SD0398 0.516 0.601SD0399 0.261 0.389 SD0400 0.327 0.300 SD0401 0.230 0.250 SD0402 0.2310.260 SD0403 0.237 0.221 SD0404 0.258 0.243 SD0405 0.253 0.246 SD04060.228 0.230 SD0407 0.228 0.215 SD0408 0.247 0.255 SD0409 0.565 0.667SD0410 0.796 0.863 SD0411 0.633 0.646 SD0412 0.613 0.699 SD0413 0.2940.439 SD0414 0.416 0.310 SD0415 0.275 0.238 SD0416 0.241 0.290 SD04170.257 0.284 SD0418 0.267 0.306 SD0419 0.249 0.229 SD0420 0.243 0.240SD0421 0.250 0.241 SD0422 0.230 0.237 SD0423 0.555 0.684 SD0424 0.6140.682 SD0425 0.592 0.733 SD0426 0.604 0.699 SD0427 0.281 0.449 SD04280.301 0.330 SD0429 0.230 0.261 SD0430 0.241 0.273 SD0431 0.232 0.255SD0432 0.247 0.288 SD0433 0.238 0.280 SD0434 0.224 0.293 SD0435 0.2490.240 SD0436 0.428 0.445 SD0437 0.542 0.829 SD0438 1.106 1.048 SD04390.930 1.096 SD0440 1.033 1.023 SD0441 0.630 0.657 SD0442 0.912 0.913SD0443 0.392 0.375 SD0444 0.552 0.441 SD0445 0.561 0.514 SD0446 0.5500.442 SD0447 0.415 0.362 SD0448 0.566 0.503 SD0449 0.579 0.475 SD04500.463 0.424 SD0451 0.925 0.929 SD0452 0.963 0.939 SD0453 0.967 0.952SD0454 0.948 0.883 SD0455 0.746 0.645 SD0456 0.840 0.860 SD0457 0.4730.402 SD0458 0.555 0.514 SD0459 0.566 0.472 SD0460 0.609 0.478 SD04610.408 0.355 SD0462 0.630 0.532 SD0463 0.631 0.497 SD0464 0.549 0.510SD0465 0.966 0.809 SD0466 0.910 0.841 SD0467 0.904 0.878 SD0468 0.9991.009 SD0469 0.734 0.760 SD0470 0.925 0.806 SD0471 0.559 0.482 SD04720.572 0.543 SD0473 0.652 0.594 SD0474 0.621 0.598 SD0475 0.564 0.472SD0476 0.769 0.631 SD0477 0.734 0.613 SD0478 0.460 0.411 SD0479 0.7130.802 SD0480 0.883 0.892 SD0481 0.926 0.899 SD0482 1.180 0.937 SD04830.805 0.986 SD0484 0.920 1.104 SD0485 0.510 0.524 SD0486 0.626 0.598SD0487 0.628 0.640 SD0488 0.597 0.637 SD0489 0.482 0.486 SD0490 0.6850.664 SD0491 0.650 0.662 SD0492 0.454 0.490 SD0493 1.006 1.040 SD04940.933 1.024 SD0495 0.927 1.016 SD0496 0.921 1.004 SD0497 0.690 0.846SD0498 0.970 0.913 SD0499 0.448 0.399 SD0500 0.614 0.485 SD0501 0.6090.521 SD0502 0.626 0.526 SD0503 0.493 0.410 SD0504 0.727 0.551 SD05050.688 0.541 SD0506 0.319 0.338 SD0507 0.927 0.897 SD0508 0.929 0.972SD0509 0.853 0.925 SD0510 0.755 0.935 SD0511 0.480 0.559 SD0512 0.8340.854 SD0513 0.440 0.323 SD0514 0.415 0.414 SD0515 0.442 0.343 SD05160.422 0.341 SD0517 0.346 0.320 SD0518 0.488 0.420 SD0519 0.435 0.390SD0520 0.819 0.737 SD0521 1.058 0.903 SD0522 1.088 0.933 SD0523 1.0750.948 SD0524 1.067 0.900 SD0525 0.917 0.858 SD0526 1.126 1.055 SD05270.832 0.776 SD0528 0.980 0.886 SD0529 1.059 0.821 SD0530 0.934 0.844SD0531 0.832 0.883 SD0532 0.936 0.868 SD0533 0.900 0.946 SD0534 1.0120.984 SD0535 1.041 1.095 SD0536 1.113 1.097 SD0537 1.125 0.957 SD05381.059 1.162 SD0539 0.901 0.963 SD0540 0.900 0.924 SD0541 1.033 0.911SD0542 0.958 0.906 SD0543 0.870 0.816 SD0544 1.100 0.853 SD0545 0.8810.794 SD0546 0.897 0.813 SD0547 1.005 0.785 SD0548 0.972 0.866 SD05491.019 1.121 SD0550 0.986 1.015 SD0551 0.966 1.033 SD0552 0.893 1.028SD0553 0.976 0.998 SD0554 0.938 0.935 SD0555 0.886 0.875 SD0556 1.1811.142 SD0557 1.016 0.999 SD0558 1.026 0.968 SD0559 0.928 0.844 SD05600.990 0.805 SD0561 0.836 0.791 SD0562 1.021 0.772 SD0563 0.886 0.946SD0564 1.194 1.254 SD0565 1.010 1.033 SD0566 1.110 0.993 SD0567 0.9950.895 SD0568 0.964 0.901 SD0569 0.853 0.876 SD0570 0.832 0.860 SD05711.036 0.959 SD0572 1.013 0.902 SD0573 0.948 0.793 SD0574 0.868 0.812SD0575 0.946 0.712 SD0576 0.922 0.774 SD0577 0.824 0.800 SD0578 0.9970.950 SD0579 1.048 1.143 SD0580 1.071 0.935 SD0581 0.987 0.869 SD05820.946 0.816 SD0583 0.932 0.789 SD0584 1.062 0.866 SD0585 1.155 0.891SD0586 0.960 0.819 SD0587 0.934 0.832 SD0588 1.033 0.781 SD0589 0.9720.798 SD0590 0.925 0.704 SD0591 1.061 0.915 SD0592 1.129 0.996 SD05930.856 0.895 SD0594 0.840 0.956 SD0595 0.882 0.857 SD0596 0.856 0.896SD0597 0.869 0.697 SD0598 0.878 0.700 SD0599 0.808 0.857 SD0600 0.8560.823 SD0601 0.742 0.713 SD0602 0.740 0.846 SD0603 0.808 0.816 SD06040.561 0.527 SD0605 0.711 0.880 SD0606 0.852 0.922 SD0607 0.695 0.887SD0608 0.635 0.917 SD0609 0.655 0.874 SD0610 0.596 0.765 SD0611 0.4820.508 SD0612 0.629 0.578 SD0613 0.616 0.503 SD0614 0.716 0.682 SD06150.570 0.491 SD0616 0.671 0.668 SD0617 0.713 0.721 SD0618 0.819 0.862SD0619 0.925 0.968 SD0620 0.859 0.978 SD0621 0.923 1.075 SD0622 0.9000.988 SD0623 0.908 0.969 SD0624 0.775 0.889 SD0625 0.827 0.850 SD06260.832 0.796 SD0627 0.916 0.796 SD0628 0.863 0.898 SD0629 0.915 0.869SD0630 0.893 0.856 SD0631 0.940 0.848 SD0632 0.878 0.911 SD0633 0.9341.074 SD0634 0.915 1.019 SD0635 0.911 0.912 SD0636 0.852 0.911 SD06370.997 0.965 SD0638 0.983 0.935 SD0639 0.806 0.823 SD0640 0.838 0.846SD0641 0.906 0.861 SD0642 0.740 0.836 SD0643 0.739 0.725 SD0644 0.7800.762 SD0645 0.739 0.819 SD0646 0.734 0.798 SD0647 0.789 0.913 SD06480.707 0.946 SD0649 0.943 1.077 SD0650 0.729 0.872 SD0651 0.666 0.879SD0652 0.704 0.882 SD0653 0.661 0.726 SD0654 0.751 0.881 SD0655 0.7270.822 SD0656 0.746 0.839 SD0657 0.849 0.842 SD0658 0.835 0.796 SD06590.972 0.830 SD0660 0.772 0.672 SD0661 0.883 0.918 SD0662 0.934 0.952SD0663 0.974 0.891 SD0664 0.939 0.936 SD0665 1.116 0.919 SD0666 0.9240.954 SD0667 0.780 0.744 SD0668 0.795 0.726 SD0669 0.819 0.754 SD06700.856 0.830 SD0671 0.844 0.758 SD0672 0.978 0.952 SD0673 0.860 0.845SD0674 0.526 0.566 SD0675 0.661 0.961 SD0676 0.690 0.916 SD0677 0.6720.939 SD0678 0.821 0.973 SD0679 0.943 0.952 SD0680 1.018 0.991 SD06810.561 0.580 SD0682 0.777 0.688 SD0683 0.654 0.639 SD0684 0.691 0.622SD0685 0.518 0.555 SD0686 0.661 0.738 SD0687 0.722 0.644 SD0688 0.4160.385 SD0689 0.571 0.870 SD0690 0.697 0.946 SD0691 0.616 0.840 SD06920.644 0.850 SD0693 0.781 0.733 SD0694 1.022 0.902 SD0695 0.458 0.448SD0696 0.500 0.455 SD0697 0.454 0.444 SD0698 0.497 0.467 SD0699 0.3690.416 SD0700 0.622 0.552 SD0701 0.542 0.528 SD0702 0.301 0.423 SD07030.376 0.367 SD0704 0.373 0.334 SD0705 0.315 0.347 SD0706 0.339 0.351SD0707 0.245 0.263 SD0708 0.572 0.703 SD0709 0.313 0.484 SD0710 0.2970.431 SD0711 0.284 0.397 SD0712 0.300 0.471 SD0713 0.297 0.417 SD07140.300 0.438 SD0715 0.280 0.430

Example 5. In Vivo Analysis of RNAi Agent Efficacy in TransientlyTransgenic and Transgenic Mice

A) Administration and Sample Collection.

In order to evaluate the efficacy of LPA RNAi agents in vivo,transiently transgenic mice were used. At least 30 days prior tocholesterol-conjugated LPA RNAi agent administration, wild-type micewere injected by hydrodynamic tail vein injection with a plasmidcontaining the SEAP gene under the control of the mouse albuminpromoter. LPA gene target sequences were cloned in the 3′ UTR of theplasmid. These mice are noted as SEAP-LPA HTV mice.Cholesterol-conjugated LPA RNAi agents were administered to mice usingMLP delivery polymer on day 1 (WO 2012/083185, incorporated herein byreference; melittin was synthesized and modified with CDM-NAG to yieldMLP delivery polymer as described therein). Each mouse received anintravenous (IV) injection into the tail vein of 200-250 μL solutioncontaining a dose of LPA RNAi agent+MLP delivery polymer (1:1 w/w RNAiagent: MLP delivery polymer in most cases). In some experiments, LPARNAi agents were directly conjugated to a delivery polymer. Polymerconjugated LPA RNAi agents were similarly injected into tail vein. Theindicated LPA RNAi agent (Table 8B) was conjugated to a polyacrylatepolymer, ARF1164-106A-5, having 54.4% ethoxy ethyl amino acrylate (EEAA)amine monomers and 45.6% propyl acrylate propyl monomers (MW 41962g/mol, polymer synthesized as described in WO 2013/158141) and maskedwith 3×ACit-NAG, 6×ACit-PEG (polymer masked as described in WO2012/092373 and PCT/US16/34512). Control serum (pre-treatment) sampleswere taken from the mice pre-injection on days −4, or −1. Post injectionserum samples were taken from the mice days 4, 8, 15, 22, 29, 36, and43. For some mice, samples were collected on day 3 or day 5, instead ofday 4.

In additional experiments, LPA RNAi agents were evaluated in vivo usingtransiently transgenic mice expressing full length LPA. At least 30 daysprior to cholesterol-targeted LPA RNAi agent administration, immunecompromised (Nod.scid) mice were injected by hydrodynamic tail veininjection with a minicircle containing the LPA cDNA under the control ofthe mouse albumin promoter. These mice are noted as LPA mc HTV mice.Either cholesterol-targeted or NAG (also termed GalNAc)-conjugated LPARNAi agents were administered to mice on day 1. For Cholesterol-targetedRNAi agents, each mouse received an intravenous (IV) injection into thetail vein of 200-250 μL solution containing a dose of RNAi agent+MLPdelivery polymer (1:1 w/w RNAi agent:MLP delivery polymer). For NAGconjugated LPA RNAi agents, mice received a subcutaneous (SC) injectioninto the loose skin on the back between the shoulders of 300 μl solutioncontaining a dose of the RNAi agent in buffered saline. For some sample,the LPA RNAi agent was administered either with or without MLP deliverypeptide. RNAi agents delivered with MLP delivery peptide wereadministered by intravenous (IV) injection into the tail vein of 200-250μL solution containing a dose of RNAi agent+MLP delivery polymer (1:2w/w RNAi agent:MLP delivery polymer in most cases). Control serum(pre-treatment) samples were taken from the mice pre-injection on days−4, or −1. Post injection serum samples were taken from the mice days 4,8, 15, 22, 29, 36, and 43. For some mice, samples were collected on day3 or day 5, instead of day 4.

In further experiments, LPA RNAi agents were administered to apo(a) andLp(a) transgenic mice (Frazer K A et al 1995, Nature Genetics9:424-431). This mouse expresses human apo(a) from a YAC containing thefull LPA gene (encoding apo(a) protein) with additional sequences both5′ and 3′. Lp(a) mice were bred by crossing apo(a) YAC-containing miceto human apoB-100 expressing mice (Callow M J et al 1994, PNAS91:2130-2134). Cholesterol-targeted RNAi agents and NAG conjugated RNAiagents were administered as described above. Control serum(pre-treatment) samples were taken from the mice pre-injection on day−1. Post injection serum samples were taken from the mice days 4, 8, 15,22, 29, 36, 43, 50, 57 and 64.

B) LPA Expression Knockdown Analyses.

For SEAP-LPA HTV mice, SEAP protein levels in serum were monitored byassaying serum from the mice using Phospha-Light, a chemiluminescentreporter gene assay system (Life Technologies). For normalization, SEAPlevel for each animal at a given time point was divided by thepre-treatment level of expression in that animal to determine the ratioof expression “normalized to pre-treatment”. Expression at a specifictime point was then averaged amongst individuals within the group.

For LPA mc HTV mice and transgenic mice, human apo(a) protein levels inserum were monitored by assaying serum from mice using an ELISA forapo(a) (Abcam). For normalization, apo(a) level for each animal at atime point was divided by the pre-treatment level of expression in thatanimal (in this case at day 1) to determine the ratio of expression“normalized to day 1”. Expression at a specific time point was thennormalized to the saline control group by dividing the “normalized today 1” ratio for an individual animal by the mean “normalized to day 1”ratio of all mice in the saline control group. This resulted inexpression for each time point normalized to that in the control group.

Lp(a) levels were determined on a Cobas Integra 400 (Roche Diagnostics)according to the manufacturer's recommendations. For normalization,apo(a) level for each animal at a time point was divided by thepre-treatment level of expression in that animal (in this case at day 1)to determine the ratio of expression “normalized to day 1”. Expressionat a specific time point was then normalized to the saline control groupby dividing the “normalized to day 1” ratio for an individual animal bythe mean “normalized to day 1” ratio of all mice in the saline controlgroup. This resulted in expression for each time point normalized tothat in the control group.

TABLE 8A Relative LPA levels in mouse following intravenousadministration of cholesterol-conjugated LPA RNAi agents + MLP deliverypolymer. LPA RNAi MLP Relative Duplex ID agent (mg/kg) (mg/kg) LPAAD01184 2 2 0.20 AD01187 2 2 0.18 AD01190 2 2 0.17 AD01193 2 2 0.22AD01196 2 2 0.02 AD01197 2 2 0.065 AD01198 2 2 0.051 AD01199 2 2 0.070AD01200 2 2 0.094 AD01201 2 2 0.029 AD01202 8 8 0.14 AD01205 2 2 0.21AD01206 2 2 0.37 AD01207 2 2 0.19 AD01208 2 2 0.35 AD01209 2 2 0.16AD01210 2 2 0.18 AD01211 2 2 0.38 AD01212 2 2 0.26 AD01213 2 2 0.30AD02662 2 2 0.0010 AD02663 2 2 0.010 AD02664 2 2 0.0010

TABLE 8B Relative LPA levels in mouse following intravenousadministration of delivery polymer-conjugated LPA RNAi agents. DuplexLPA RNAi agent Relative ID (mg/kg) LPA AD01462 0.5 0.38 AD01463 0.5 0.41AD01466 0.5 0.33 AD01467 0.5 0.46

TABLE 8C Relative LPA levels in mouse following subcutaneousadministration of NAG-conjugated LPA RNAi agents. LPA RNAi agentRelative Duplex ID (mg/kg) LPA AD01529 10 0.068 AD01530 10 0.43 AD0153110 0.62 AD01532 10 0.18 AD01533 10 0.30 AD01534 10 0.44 AD01765 10 0.14AD01766 10 0.52 AD01767 10 0.51 AD01768 10 0.15 AD01769 10 0.56 AD0177010 0.29 AD01772 10 0.25 AD01773 10 0.28 AD01774 10 0.24 AD01780 10 0.34AD01804 10 0.68 AD01976 10 0.27 AD01977 10 0.27 AD01978 10 0.53 AD0197910 0.044 AD01980 10 0.087 AD01981 10 0.074 AD01982 10 0.066 AD01983 100.078 AD01984 10 0.036 AD01985 10 0.0070 AD01986 10 0.019 AD01987 100.019 AD01988 10 0.042 AD01989 10 0.053 AD01990 10 0.017 AD02001 100.021 AD02003 10 0.050 AD02004 10 0.050 AD02005 10 0.040 AD02006 10 0.11AD02007 10 0.21 AD02008 10 0.080 AD02009 10 0.090 AD02010 10 0.16AD02011 10 0.070 AD02435 10 0.038 AD02436 10 0.027 AD02437 10 0.052AD02438 10 0.063 AD02439 10 0.073 AD02440 10 0.13 AD02545 10 0.079AD02546 10 0.045 AD02547 10 0.055 AD02548 10 0.13 AD02549 10 0.071AD02550 10 0.039 AD02551 10 0.057 AD02552 10 0.033 AD02553 10 0.14AD02554 10 0.14 AD02555 10 0.18 AD02556 10 0.10 AD02557 10 0.10 AD0255810 0.071 AD02559 10 0.039 AD02560 10 0.058 AD02561 10 0.12 AD02609 30.59 AD02610 3 0.36 AD02611 3 0.35 AD02612 3 0.37 AD02613 3 0.24 AD026143 0.24 AD02615 3 0.14 AD02616 3 0.25 AD02617 3 0.090 AD02618 3 0.11AD02619 3 0.020 AD02620 3 0.11 AD02682 10 0.11 AD02683 10 0.14 AD0268410 0.79 AD02685 10 0.78 AD02686 10 0.19 AD02687 10 0.27 AD02696 3 0.050AD02710 3 0.040 AD02711 3 0.040 AD02712 3 0.49 AD02713 3 0.040 AD02714 30.040 AD02715 3 0.070 AD02716 3 0.080 AD02717 3 0.12 AD02745 3 0.25AD02746 3 0.22 AD02747 3 0.081 AD02748 3 0.17 AD02749 3 0.17 AD02750 30.066 AD02751 3 0.070 AD02752 3 0.044 AD02753 3 0.071 AD02819 1 0.022AD02820 1 0.042 AD02821 1 0.038 AD02825 3 0.050 AD02826 3 0.050 AD028273 0.050 AD02828 3 0.050 AD02829 3 0.040 AD02830 3 0.040 AD02831 3 0.030AD02832 3 0.030 AD02841 3 0.061 AD02842 3 0.16 AD02843 3 0.10 AD02844 30.11 AD02845 3 0.22 AD02846 3 0.16 AD02847 3 0.066 AD02848 3 0.055AD02849 3 0.083 AD02850 3 0.042 AD02851 3 0.063 AD02852 3 0.11 AD0290710 0.10 AD02908 10 0.11 AD02909 10 0.049 AD02910 10 0.23 AD02911 10 0.20AD02912 10 0.10 AD02913 10 0.070 AD02914 10 0.050 AD02915 10 0.10AD02916 10 0.090 AD02917 10 0.060 AD02918 10 0.020 AD02919 10 0.030AD02920 10 0.050 AD02921 10 0.040 AD02922 10 0.080 AD02923 10 0.040AD02924 10 0.050 AD02925 10 0.030 AD02926 10 0.17 AD02927 10 0.31AD02928 10 0.081 AD02929 10 0.065 AD02930 10 0.15 AD02931 10 0.13AD02932 10 0.11 AD03049 3 0.20 AD03050 3 0.087 AD03051 3 0.070 AD03052 30.080 AD03053 3 0.23 AD03054 3 0.050 AD03058 3 0.27 AD03059 3 0.22AD03060 3 0.31 AD03061 3 0.16 AD03062 3 0.20 AD03063 3 0.13 AD03064 30.21 AD03065 3 0.085 AD03066 3 0.10 AD03067 3 0.094 AD03068 3 0.17AD03069 3 0.077 AD03070 3 0.36 AD03071 3 0.043 AD03072 3 0.031 AD03073 30.019 AD03074 3 0.016 AD03075 3 0.062 AD03114 1 0.33 AD03115 1 0.30AD03116 1 0.21 AD03117 1 0.14 AD03118 1 0.30 AD03119 1 0.10 AD03120 10.080 AD03121 1 0.14 AD03122 1 0.14 AD03123 1 0.34 AD03156 1 0.084AD03157 1 0.016 AD03158 1 0.037 AD03159 1 0.63 AD03272 1 0.13 AD03273 10.20 AD03274 1 0.21 AD03275 1 0.15 AD03276 1 0.11 AD03277 1 0.13 AD032781 0.13 AD03279 1 0.21 AD03341 1 0.13 AD03421 1 0.29 AD03430 1 0.12AD03432 1 0.16 AD03434 1 0.11 AD03436 1 0.21 AD03438 1 0.25 AD03440 10.21 AD03460 1 0.090 AD03462 1 0.40 AD03495 1 0.28 AD03536 1 0.14AD03538 0.5 0.26 AD03539 0.5 0.21 AD03540 1 0.15 AD03541 0.5 0.10AD03542 1 0.94 AD03547 1 0.19 AD03548 1 0.73 AD03549 1 0.29 AD03573 10.15 AD03574 1 0.15 AD03575 1 0.13 AD03576 1 0.18 AD03577 0.5 0.18AD03578 0.5 0.38 AD03579 0.5 0.53 AD03603 1 0.083 AD03604 1 0.091AD03605 1 0.19 AD03608 1 0.18 AD03609 1 0.16 AD03610 1 0.23 AD03611 10.40 AD03612 1 0.21 AD03629 1 0.11 AD03668 1 0.070 AD03705 0.5 0.11AD03707 0.5 0.11 AD03720 0.5 0.14 AD03721 0.5 0.094 AD03722 0.5 0.19AD03723 0.5 0.10 AD03765 1 0.080 AD03771 1 0.10 AD03801 1 0.15 AD03802 10.18 AD03844 1 0.17 AD03845 1 0.25 AD03848 1 0.10 AD03850 1 0.052AD03851 1 0.076 AD03852 1 0.13 AD03853 1 0.081 AD03854 1 0.21 AD03856 10.32 AD03859 1 0.15 AD03862 1 0.12 AD03863 1 0.12 AD03921 1 0.17 AD039221 0.057 AD03923 1 0.066 AD03924 1 0.14 AD03931 1 0.34 AD03932 1 0.15AD03933 1 0.34 AD03424 1 0.15 AD03425 1 0.21 AD03426 1 0.21 AD03427 10.19 AD03428 1 0.18 AD03760 0.5 0.21 AD03762 0.5 0.17 AD03763 0.5 0.21AD03764 0.5 0.28 AD03766 0.5 0.065 AD03847 1 0.15 AD04110 1 0.070

Example 6. In Vivo Screening of LPA RNAi Agents and Time Course of SEAPKnockdown

Cholesterol-conjugated LPA RNAi agents were administered to transientlytransgenic mice as described above. Each mouse received a singleintravenous (IV) dose of 8 mg/kg of LPA RNAi agent with 8 mg/kg of MLPdelivery polymer. SEAP protein levels in serum were monitored for up to36 days. Knockdown levels and duration of response are shown in Table 9.A decrease in SEAP serum protein level of greater than 85% was obtainedfollowing administration of all LPA RNAi agents tested; with all but twoLPA RNAi agents tested showing greater than 99.4% knockdown. AD01196 andAD01199 showed >95% knockdown at day 36.

Example 7. In Vivo Screening LPA RNAi Agents and Time Course of LPAKnockdown at Lower LPA RNAi Agent Doses

Cholesterol-conjugated LPA RNAi agents were administered to transientlytransgenic mice as described above. Each mouse received a singleintravenous (IV) dose of 2 mg/kg of LPA RNAi agent with 2 mg/kg of MLPdelivery polymer. SEAP protein levels in serum were monitored for up to43 days (Table 10).

Example 8. In Vivo Testing of LPA RNAi Agents in Apo(a) Transgenic (Tg)Mice

AD01196 was administered to mice as described above. Each mouse receiveda single intravenous (IV) dose of either 2 mg/kg of LPA RNAi agent with2 mg/kg of MLP delivery polymer or saline. Human apo(a) (apo(a)) levelsin serum were monitored for up to 64 days (Table 11). At day 15, animalsin the saline group received a single IV dose of 2 mg/kg of a controlmouse Factor VII (F7) RNAi agent with 2 mg/kg of MLP delivery polymer.At day 22, F7 levels were measured in all animals. F7 activity wasknocked down by 99% 7 days post dosing, with no effect on serum apo(a)levels. AD01196 showed >3 log 10 knockdown of apo(a) levels at nadir,with >80% knockdown observed after 3 weeks (Table 11).

TABLE 9 Serum SEAP protein levels in SEAP-LPA HTV mice followingadministration of 8 mg/kg chol-RNAi agents with 8 mg/kg MLP deliverypeptide. SEAP levels were normalized to day −1 and saline control. Day−1 Day 4 Day 8 Day 15 Day 22 Day 29 Day 36 Treatment Ave SD Ave SD AveSD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.24 1.00 0.34 1.00 0.13 1.000.33 1.00 0.09 1.00 0.18 1.00 0.44 AD01184 1.00 0.39 0.27 0.10 0.15 0.060.01 0.00 0.07 0.04 0.43 0.39 0.98 0.73 AD01187 1.00 0.53 0.24 0.15 0.130.10 0.00 0.00 0.01 0.01 0.08 0.06 0.56 0.47 AD01190 1.00 0.77 0.26 0.200.14 0.11 0.00 0.00 0.00 0.00 0.00 0.00 0.02 0.01 AD01193 1.00 0.99 0.250.26 0.15 0.17 0.01 0.01 0.00 0.00 0.01 0.01 0.02 0.01 AD01196 1.00 0.590.24 0.13 0.14 0.08 0.00 0.00 0.00 0.00 0.01 0.01 0.04 0.03 AD01199 1.000.52 0.23 0.15 0.13 0.10 0.00 0.00 0.00 0.00 0.01 0.00 0.04 0.02 AD012021.00 0.93 0.25 0.24 0.17 0.16 0.14 0.12 0.56 0.55 0.78 0.66 2.09 2.00

TABLE 10 Serum SEAP protein levels in SEAP-LPA HTV mice followingadministration of 2 mg/kg chol-RNAi agents with 2 mg/kg MLP deliverypeptide. SEAP levels were normalized to day −1 and saline control. Day−4 Day 4 Day 9 Day 15 Day 22 Day 29 Day 36 Day 43 Treatment Ave. SD Ave.SD Ave. SD Ave. SD Ave. SD Ave. SD Ave. SD Ave. SD Saline 1.00 0.00 1.000.72 1.00 0.72 1.00 0.71 1.00 0.43 1.00 0.79 1.00 0.48 1.00 0.54 AD011961.00 0.00 0.22 0.08 0.05 0.05 0.02 0.01 0.13 0.04 0.36 0.12 0.69 0.081.39 0.91 AD01199 1.00 0.00 0.27 0.28 0.07 0.06 0.17 0.17 0.59 0.51 0.740.74 0.83 0.82 1.01 0.58 AD01205 1.00 0.00 0.21 0.13 0.31 0.23 0.45 0.211.33 0.68 1.11 0.82 1.55 1.30 1.79 1.09 AD01208 1.00 0.00 0.43 0.20 0.350.15 0.68 0.19 1.45 0.44 1.32 0.26 1.39 0.52 0.99 0.12 AD01211 1.00 0.000.38 0.14 0.53 0.20 0.94 0.38 1.96 0.93 1.05 0.27 1.44 0.38 0.93 0.28AD01184 1.00 0.00 0.26 0.07 0.20 0.05 0.61 0.17 1.28 0.14 1.21 0.51 1.390.80 ND ND AD01187 1.00 0.00 0.37 0.18 0.09 0.07 0.18 0.17 0.86 0.840.77 0.33 1.80 0.36 ND ND AD01190 1.00 0.00 0.26 0.08 0.17 0.07 0.360.13 1.16 0.37 1.39 0.69 1.96 1.64 ND ND AD01193 1.00 0.00 0.39 0.270.22 0.33 0.32 0.37 0.67 0.58 0.84 0.46 1.27 0.23 ND ND

TABLE 11 Serum apo(a) protein levels in apo(a) Tg mice followingadministration of 2 mg/kg cholesterol-conjugated LPA RNAi agent with 2mg/kg MLP delivery polymer. Apo(a) levels were normalized to day −1 andsaline control. Day −1 Day 4 Day 8 Day 15 Day 22 Treatment Ave SD Ave SDAve SD Ave SD Ave SD Saline 1.00 0.00 1.00 0.06 1.00 0.27 1.00 0.06 1.000.17 AD01196 1.00 0.00 0.00 0.00 0.00 0.00 0.01 0.00 0.15 0.08 Day 29Day 36 Day 43 Day 50 Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.12 1.000.04 1.00 0.26 1.00 0.24 AD01196 0.40 0.23 0.74 0.61 0.75 0.67 0.77 0.52

Example 9. Apolipoprotein (a) (Apo(a)) Knockdown in Non-Human PrimatesFollowing LPA RNAi Agent Delivery by MLP Delivery Polymer

MLP delivery polymer and LPA RNAi agent were made and combined in apharmaceutically acceptable buffer as described above. On day 1, twocynomolgus macaque (Macaca fascicularis) primates (both male, 5.0 kg and8.15 kg, respectively) were injected with 2 mg/kg AD01196+2 mg/kg MLPdelivery polymer. For each injection, the LPA RNAi agent+MLP deliverypolymer (2 ml/kg) was injected into the saphenous vein using a 22 to 25gauge intravenous catheter. At the indicated time points (indicated inTable 12), blood samples were drawn and analyzed for apo(a) levels,lipid levels and toxicity markers. Blood was collected from the femoralvein and primates were fasted overnight before all blood collections.Blood tests for blood urea nitrogen (BUN), alanine transaminase (ALT),aspartate aminotransferase (AST), creatinine, total cholesterol (TC) andtriglycerides (TG) were performed on an automated chemistry analyzer atMeriter laboratories. Blood tests for Lipoprotein (a) (Lp(a)) and Lowdensity lipoprotein (LDL) were measured on an automated chemistryanalyzer. Serum apo(a) levels were measured by ELISA. Significantknockdown of apo(a) was observed with an average maximum knockdown of94.5% observed at day 22. Average maximum knockdown of Lp(a) was 91.5%observed at day 15 (FIG. 3). No dose-related toxicity was observed intreated animals.

TABLE 12 Serum apo(a) protein, Lipoprotein(a) (mg/dL), Low densityLipoprotein (LDL), Total cholesterol, and triglyceride levels incynomolgus macaque (Macaca fascicularis) primates followingadministration of 2 mg/kg AD01196 with 2 mg/kg MLP delivery polymer.Apo(a) levels were normalized to predose. Low Density Total Serum apo(a)Lipoprotein(a) Lipoprotein Cholesterol Triglycerides protein levelslevels (mg/dL) calculated (mg/dL) (mg/dL) (mg/dL) day animal 1 animal 2animal 1 animal 2 animal 1 animal 2 animal 1 animal 2 animal 1 animal 2pre 1.00 1.00 77.1 126.7 48.4 84.7  95 149 41 36 3 0.47 0.55 46.0 65.053.6 83.5  93 143 33 28 8 0.12 0.15 9.3 16.5 53.4 75.9 101 147 36 30 150.10 0.10 5.0 7.3 49.8 60.9 106 136 79 34 22 0.05 0.06 7.9 10.3 47.563.9  97 136 34 36 29 0.08 0.11 13.4 27.0 55.7 47.5 101 116 20 36 360.15 0.25 22.2 50.6 56.8 73.1 — — — — 43 0.19 0.23 31.4 45.5 53.8 55.7103 138 29 39 50 0.27 0.29 46.1 67.3 52.3 70.9 — — — — 57 0.27 0.3 52.769.7 52.1 78.6 104 157 34 39 64 0.33 0.31 68.4 73.7 52.4 75.8 — — — — 710.50 0.4 76.8 78.6 62.4 75.0 104 149 43 47 85 0.31 0.34 63.1 75.4 50.368.8 102 145 41 49 99 0.27 0.29 67.9 78.8 58.7 72.5 102 150 42 52 1200.36 0.37 91.7 119.4 53.4 79.8 100 154 43 51

TABLE 13 Urea Nitrogen, Creatinine, Alanine transaminase, and Aspartateaminotransferase levels in cynomolgus macaque (Macaca fascicularis)primates following administration of 2 mg/kg AD01196 with 2 mg/kg MLPdelivery polymer. Alanine Aspartate Blood Urea Creatinine transaminaseaminotransferase Nitrogen (mg/dL) (mg/dL) (U/L) (U/L) day animal 1animal 2 animal 1 animal 2 animal 1 animal 2 animal 1 animal 2 predose16 16 0.79 0.70 37 32 32 33 3 11 14 0.70 0.61 40 42 33 35 8 14 13 0.780.58 33 38 25 31 15 15 15 0.67 0.59 51 35 47 32 22 15 15 0.8  0.55 47 3529 30 29 12 12 0.61 0.59 30 31 23 36 36 — — — — — — — — 43 12 15 0.640.58 29 29 25 30 50 — — — — — — — — 57 14 15 0.72 0.64 32 35 28 31 64 —— — — — — — — 71 14 15 0.73 0.69 36 35 29 33 85 14 15 0.60 0.70 126  4151 40 99 15 18 0.66 0.68 151  40 44 37 120 14 19 0.72 0.60 37 51 28 47

Example 10. In Vive Screening of NAG-Conjugated LPA RNAi Agents and TimeCourse of Knockdown

NAG-conjugated LPA RNAi agents were administered to transientlytransgenic mice as described above. Each mouse received either singleintravenous (IV) dose of 2 mg/kg of LPA RNAi agent with 1 mg/kg of MLPdelivery polymer, or a single subcutaneous (SC) dose of 10 mg/kg of theNAG-conjugated LPA RNAi agent. SEAP protein levels in serum weremonitored for up to 22 days. Knockdown levels and duration of responseare shown in Tables 14-15. AD01529, AD01532 and AD01533 showed >85%knockdown of SEAP levels following IV administration with MLP deliverpolymer, and 260% maximum knockdown of SEAP levels following SCadministration of the NAG-conjugated LPA RNAi agent alone.

TABLE 14 Serum SEAP protein levels in SEAP-LPA HTV mice following SCadministration of 10 mg/kg NAG-conjugated LPA RNAi agents. SEAP levelswere normalized to day −1 and saline control. Day −1 Day 4 Day 8 Day 15Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.001.00 0.14 1.00 0.14 1.00 0.66 1.00 0.27 AD01529 1.00 0.00 0.45 0.07 0.360.03 0.60 0.08 0.90 0.37 AD01530 1.00 0.00 0.46 0.15 0.43 0.10 0.79 0.260.79 0.32 AD01531 1.00 0.00 0.64 0.13 0.62 0.06 0.99 0.28 1.17 0.29AD01532 1.00 0.00 0.41 0.12 0.37 0.11 0.99 0.34 1.33 0.11 AD01533 1.000.00 0.40 0.03 0.22 0.08 0.37 0.15 0.63 0.13 AD01534 1.00 0.00 0.65 0.190.44 0.19 0.74 0.30 1.17 0.55

TABLE 15 Serum SEAP protein levels in SEAP-LPA HTV mice following IVadministration of 1 mg/kg NAG-conjugated LPA RNAi agents + 2 mg/kg MLPdelivery polymer. SEAP levels were normalized to day −1 and salinecontrol. Day −1 Day 4 Day 8 Day 15 Day 22 Treatment Ave SD Ave SD Ave SDAve SD Ave SD Saline 1.00 0.00 1.00 0.33 1.00 0.46 1.00 0.21 1.00 0.39F7 Control 1.00 0.00 0.61 0.05 0.71 0.45 1.25 0.44 1.05 0.49 AD015291.00 0.00 0.25 0.04 0.15 0.08 0.47 0.24 0.81 0.40 AD01530 1.00 0.00 0.260.06 0.28 0.19 0.78 0.60 1.06 0.63 AD01531 1.00 0.00 0.22 0.07 0.26 0.060.72 0.21 1.04 0.12 AD01532 1.00 0.00 0.18 0.05 0.06 0.03 0.13 0.08 0.290.18 AD01533 1.00 0.00 0.21 0.04 0.13 0.06 0.32 0.15 0.67 0.28 AD015341.00 0.00 0.17 0.04 0.22 0.06 0.66 0.24 0.94 0.24

Example 11. In Vivo Screening of Modified NAG-Conjugated LPA RNAi Agentsand Time Course of Knockdown

The indicated NAG-conjugated LPA RNAi agents were administered toSEAP-LPA HTV mice as described above. Each mouse received a singlesubcutaneous (SC) dose of 10 mg/kg of the NAG-conjugated LPA RNAi agent.SEAP protein levels in serum were monitored for up to 22 days. Knockdownlevels and duration of response are shown in Tables 16-17. AD01765 andAD01768 showed 89% knockdown activity.

TABLE 16 Serum SEAP protein levels in SEAP-LPA HTV mice following SCadministration of 10 mg/kg NAG-conjugated LPA RNAi agent. SEAP levelswere normalized to day −1 and saline control. Day −1 Day 3 Day 8 Day 15Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.001.00 0.16 1.00 0.16 1.00 0.28 1.00 0.24 AD01533 1.00 0.00 0.41 0.08 0.220.02 0.47 0.20 0.66 0.29 AD01772 1.00 0.00 0.46 0.13 0.18 0.00 0.34 0.090.61 0.14 AD01773 1.00 0.00 0.47 0.08 0.20 0.08 0.45 0.15 0.83 0.12AD01774 1.00 0.00 0.49 0.09 0.18 0.03 0.44 0.13 0.68 0.08 AD01780 1.000.00 0.52 0.13 0.25 0.09 0.44 0.26 0.65 0.37

TABLE 17 Serum SEAP protein levels in SEAP-LPA HTV mice following SCadministration of 10 mg/kg NAG-conjugated LPA RNAi agent. SEAP levelswere normalized to day −1 and saline control. Day −1 Day 3 Day 8 Day 15Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.001.00 0.27 1.00 0.73 1.00 0.87 1.00 0.80 AD01532 1.00 0.00 0.42 0.19 0.350.21 0.85 0.25 1.27 0.57 AD01765 1.00 0.00 0.35 0.02 0.11 0.08 0.25 0.140.47 0.19 AD01766 1.00 0.00 0.52 0.10 0.36 0.09 1.05 0.13 1.15 0.08AD01767 1.00 0.00 0.49 0.03 0.44 0.05 1.43 0.23 1.33 0.71 AD01768 1.000.00 0.34 0.15 0.11 0.07 0.39 0.13 0.76 0.19 AD01769 1.00 0.00 0.54 0.170.46 0.14 1.32 0.12 1.38 0.37 AD01770 1.00 0.00 0.41 0.07 0.20 0.10 0.800.52 1.04 0.67

Example 12. In Viva Testing of NAG-Conjugated LPA RNAi Agents in Apo(a)Tg Mice

NAG-conjugated LPA RNAi agents were administered to apo(a) Tg mice asdescribed above. Each mouse received a single subcutaneous (SC) dose ofeither 10 mg/kg of LPA RNAi agent or saline. Human apo(a) (apo(a))levels in serum were monitored for up to days (Table 18). AD01765 showedthe largest knockdown of apo(a) levels at day 8 with 96% knockdown,and >74% knockdown observed 3 weeks after dosing.

TABLE 18 Serum apo(a) protein levels in apo(a) Tg mice following SCadministration of 10 mg/kg NAG-conjugated LPA RNAi agent. Apo(a) levelswere normalized to day −1 and saline control. Day −1 Day 4 Day 8 Day 15Day 22 Treatment Ave SD Ave SD Ave SD Ave SD Ave SD Saline 1.00 0.001.00 0.10 1.00 0.16 1.00 0.42 1.00 0.21 AD01532 1.00 0.00 0.12 0.05 0.220.08 0.76 0.30 0.56 0.28 AD01765 1.00 0.00 0.09 0.03 0.04 0.02 0.14 0.020.26 0.04 AD01768 1.00 0.00 0.11 0.05 0.09 0.05 0.26 0.12 0.38 0.08

Example 13. In Vivo Testing of NAG-Conjugates LPA RNAi Agents in LPA McHTV Mice

Indicated NAG-conjugated LPA RNAi agents were administered to LPA mc HTVmice as described above. Each mouse received a single subcutaneous (SC)dose of either 10 mg/kg of LPA RNAi agent or saline. Human apo(a)(apo(a)) levels in serum were analyzed at day 4 (Table 19). AD02001,AD01765 and AD01768 showed >90% knockdown at day 4.

TABLE 19 Serum apo(a) protein levels in LPA mc HTV mice following SCadministration of 10 mg/kg NAG-conjugated LPA RNAi agent. Apo(a) levelswere normalized to day −1 and saline control. Prebleed Day 4 TreatmentAve SD Ave SD saline 1.00 0.00 1.00 0.12 AD01765 1.00 0.00 0.05 0.02AD01768 1.00 0.00 0.07 0.01 AD01804 1.00 0.00 0.68 0.16 AD02001 1.000.00 0.06 0.03

Example 14. Apolpoprotein (a) (Apo(a)) Knockdown in Non-Human PrimatesFollowing LPA RNAi Agent Delivery by MLP Delivery Polymer

MLP delivery polymer and LPA RNAi agent were made and combined in apharmaceutically acceptable buffer. On day 1 and day 71, two cynomolgusmacaque (Macaca fascicularis) primates were injected with either 4 mg/kgAD01196+4 mg/kg MLP delivery polymer or 6 mg/kg AD01196+6 mg/kg MLPdelivery polymer. For each injection, the LPA RNAi agent+MLP deliverypolymer was injected into the saphenous vein using a 22 to 25 gaugeintravenous catheter. At the indicated time points (FIG. 4), bloodsamples were drawn and analyzed for apo(a) levels, lipid levels andtoxicity markers as previously described. Significant knockdown ofapo(a) was observed after the first dose with an average maximumknockdown of 96% for 4 mg/kg dose on day 15, and 96% for 6 mg/kg doseobserved at day 15. Average maximum knockdown of Lp(a) after the firstdose was 98.5% for 4 mg/kg dose on day 29, and 98.5% for 6 mg/kg dose onday 22. No dose-related toxicity was observed in treated animals.

Example 15. In Vivo Testing of NAG-Conjugated LPA RNAi Agents in Lp(a)Tg Mice-Dose Response

NAG-conjugated LPA RNAi agents were administered to Lp(a) Tg mice asdescribed above. Each mouse received a single subcutaneous (SC) dose ofeither LPA RNAi agent at 0.5 mg/kg or 2 mg/kg dose levels or saline.Lp(a) levels in serum were monitored up to day 43 (FIG. 1, FIG. 2). AllLPA RNAi agents showed dose-response with the higher doses showinggreater knockdown with nadir between days 15 and 22.

Example 16. Apolipoprotein (a) (Apo(a)) Knockdown in Non-Human PrimatesFollowing Apo(a) Specific LPA RNAi Agent Molecule Delivery

LPA RNAi agent was prepared in a pharmaceutically acceptable buffer asdescribed herein for subcutaneous (SC) injection. On days 1, 7, and 15,two cynomolgus macaque (Macaca fascicularis) primates were injectedsubcutaneously with 3 mg/kg of AD02713, AD02819, AD02820, or AD02821. Inaddition, AD02819-treated monkeys were dosed again with 3 mg/kg ofAD02819 on day 57 and day 85. Blood samples were drawn and analyzed forapo(a) levels, lipid levels and toxicity markers as previouslydescribed. Significant knockdown of Lp(a) was observed with an averagemaximum knockdown of 89% observed at day 43 for AD02713, 87% observed onday 36 for AD02819, 79% observed on day 36 for AD02820, and 95% observedon day 29 for AD02821 (FIG. 5). No dose-related toxicity was observed intreated animals over the time of the experiment.

Example 17. Apolpoprotein (a) (Apo(a)) Knockdown in Non-Human PrimatesFollowing LPA RNAi Agent Delivery

LPA RNAi agent was prepared in a pharmaceutically acceptable buffer asdescribed herein for subcutaneous (SC) injection. On day 1, twocynomolgus macaque (Macaca fascicularis) primates were injectedsubcutaneously with 3 mg/kg of AD03272, AD03462. AD03549, AD03547,AD03668, AD03460, or AD03536. In addition. AD03460 and AD03536-treatedmonkeys were dosed again with 1 mg/kg of the respective LPA RNAi agenton day 48. Blood samples were drawn and analyzed for apo(a) levels,lipid levels and toxicity markers as previously described. Significantknockdown of Lp(a) was observed with an average maximum knockdown of 62%for AD03272 on day 15, 28% for AD03462 on day 15, 47% for AD03549 on day29, 44% for AD03547 on day 15, 53% for AD03668 on day 22, 79% forAD03460 on day 29, and 71% for AD03536 on day 22 (FIG. 6). Nodose-related toxicity was observed in treated animals over the time ofthe experiment.

Example 18. Apolipoprotein (a) (Apo(a)) Knockdown in Primate FollowingApo(a) Specific LPA RNAi Agent Molecule Delivery

LPA RNAi agent was made and combined in a pharmaceutically acceptablebuffer as described above for subcutaneous (SQ) injection. On day 1,cynomolgus macaque (Macaca fascicularis) primates were injected withsubcutaneously with saline or 2 mg/kg of AD03460, AD03536, AD03851,AD03853, or AD04110. Blood samples were drawn and analyzed for apo(a)levels, lipid levels and toxicity markers on days 8 and 15 as previouslydescribed. Lp(a) levels were normalized to average of three predosevalues.

TABLE 20 Lipoprotein(a) levels in cynomolgus macaque primates followingadministration of either saline or 2 mg/kg AD03460, AD03536, AD03851,AD03853 or AD04110. Normalized Lp(a) Normalized Lp(a) Day 8 Day 15Saline 1.01 ± 0.06 1.15 ± 0.07 AD03460 0.68 ± 0.12 0.40 ± 0.13 AD035360.54 ± 0.07 0.21 ± 0.06 AD03851 0.41 ± 0.08 0.18 ± 0.08 AD03853 0.50 ±0.23 0.27 ± 0.17 AD04110 0.59 ± 0.13 0.43 ± 0.10

The invention claimed is:
 1. An LPA RNA interference (RNAi) agentcomprising: a sense strand and an antisense strand, wherein theantisense strand comprises a core sequence that is complementary to anLPA mRNA sequence, and wherein the sense strand comprises a sequencethat is complementary to the core sequence of the antisense strand; anda targeting group conjugated to the sense strand or the antisensestrand, the targeting group comprising:

wherein NAG is N-Acetyl-Galactosamine and X is selected from the groupconsisting of O and S.
 2. The LPA RNAi agent of claim 1, wherein X is O.3. The LPA RNAi agent of claim 1, wherein X is S.
 4. The LPA RNAi agentof claim 1, wherein the targeting group is conjugated to the 3′ end ofthe sense strand.
 5. The LPA RNAi agent of claim 1, wherein thetargeting group is conjugated to the 5′ end of the sense strand.
 6. TheLPA RNAi agent of claim 1, wherein the sense strand and the antisensestrand are each 19 to 26 nucleotides in length.
 7. The LPA RNAi agent ofclaim 6, wherein the sense strand and the antisense strand are each 26nucleotides in length.
 8. The LPA RNAi agent of claim 6, wherein thesense strand and the antisense strand are each 21 nucleotides in length.9. The LPA RNAi agent of claim 1, wherein the LPA RNAi agent comprisesat least one overhang.
 10. The LPA RNAi agent of claim 1, wherein theLPA RNAi agent comprises at least one blunt end.
 11. The LPA RNAi agentof claim 1, wherein the sense strand, the antisense strand, or both thesense and antisense strand comprise one or more modified nucleotides.12. The LPA RNAi agent of claim 11, wherein the one or more modifiednucleotides are independently selected from a 2′-modified nucleotide, alocked nucleotide, an abasic nucleotide, an inverted deoxynucleotide, amorpholino nucleotide, a 2′,3′-seco nucleotide mimic, or a nucleotidecontaining a non-natural base.
 13. The LPA RNAi agent of claim 11,wherein the 2′-modified nucleotide is a 2′-O-methyl nucleotide, a2′-deoxy-2′-fluoro nucleotide, a 2′-deoxynucleotide, a 2′-methoxyethylnucleotide, a 2′-amino nucleotide, or a 2′-alkyl nucleotide.
 14. The LPARNAi agent of claim 1, wherein the LPA RNAi agent comprises one or morephosphorothioate internucleoside linkages.
 15. The LPA RNAi agent ofclaim 14, wherein both the sense and antisense strand independentlycomprise 1, 2, 3, or 4 phosphorothioate internucleoside linkages. 16.The LPA RNAi agent of claim 1, wherein the core sequence comprises anyone of SEQ ID NO: 1280, SEQ ID NO: 1281, SEQ ID NO: 1282, SEQ ID NO:1283, SEQ ID NO: 1246, SEQ ID NO: 1242, SEQ ID NO: 1244, SEQ ID NO:1248, SEQ ID NO: 1250, SEQ ID NO: 1252, or SEQ ID NO:
 1254. 17. The LPARNAi agent of claim 1, wherein the sense strand comprises SEQ ID NO:1284.
 18. The LPA RNAi agent of claim 1, wherein the antisense strandcomprises SEQ ID NO: 156 and the sense strand comprises SEQ ID NO: 310.19. The LPA RNAi agent of claim 1, wherein the antisense strandcomprises SEQ ID NO: 164 and the sense strand comprises SEQ ID NO: 357.20. The LPA RNAi agent of claim 1, wherein the antisense strandcomprises SEQ ID NO: 188 and the sense strand comprises SEQ ID NO: 384.21. The LPA RNAi agent of claim 1, wherein the antisense strandcomprises SEQ ID NO: 164 and the sense strand comprises SEQ ID NO: 376.22. The LPA RNAi agent of claim 1, wherein the antisense strandcomprises SEQ ID NO: 164 and the sense strand comprises SEQ ID NO: 384.23. The LPA RNAi agent of claim 1, wherein the antisense strandcomprises the sequence of modified nucleotides according to SEQ ID NO:790 and the sense strand comprises the sequence of modified nucleotidesaccording to SEQ ID NO:
 1189. 24. The LPA RNAi agent of claim 1, whereinthe antisense strand comprises the sequence of modified nucleotidesaccording to SEQ ID NO: 637 and the sense strand comprises the sequenceof modified nucleotides according to SEQ ID NO:
 1132. 25. The LPA RNAiagent of claim 1, wherein the antisense strand comprises the sequence ofmodified nucleotides according to SEQ ID NO: 709 and the sense strandcomprises the sequence of modified nucleotides according to SEQ ID NO:1135.
 26. The LPA RNAi agent of claim 1, wherein the antisense strandcomprises the sequence of modified nucleotides according to SEQ ID NO:787 and the sense strand comprises the sequence of modified nucleotidesaccording to SEQ ID NO:
 1191. 27. The LPA RNAi agent of claim 1, whereinthe antisense strand comprises the sequence nucleotides according to SEQID NO: 788 and the sense strand comprises the sequence of modifiednucleotides according to SEQ ID NO:
 1189. 28. A pharmaceuticalcomposition comprising the LPA RNAi agent of claim 1 and apharmaceutically acceptable excipient.
 29. The pharmaceuticalcomposition of claim 28, wherein X is O.
 30. The pharmaceuticalcomposition of claim 28, wherein X is S.
 31. A method of reducing Lp(a)levels in serum of a subject, comprising administering to the subjectthe RNAi agent of claim
 16. 32. The method of claim 31, wherein X is O.33. The method of claim 31, wherein X is S.
 34. The method of claim 31,wherein the subject has heterozygous or homozygous familialhypercholesterolemia.
 35. The method of claim 31, wherein the subjecthas or is at risk of having coronary artery disease.
 36. The method ofclaim 31, wherein the subject has or is at risk of having peripheralartery disease.
 37. The method of claim 31, wherein the RNAi agent isadministered to the subject by subcutaneous or intravenous injection.38. A method for inhibiting LPA gene expression in the liver of asubject, comprising administering to the subject the RNAi agent of claim16.
 39. The method of claim 38, wherein the RNAi agent is administeredto the subject by subcutaneous or intravenous injection.